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EP4652180A2 - Peptide inhibitors of interleukin-23 receptor - Google Patents

Peptide inhibitors of interleukin-23 receptor

Info

Publication number
EP4652180A2
EP4652180A2 EP24706605.3A EP24706605A EP4652180A2 EP 4652180 A2 EP4652180 A2 EP 4652180A2 EP 24706605 A EP24706605 A EP 24706605A EP 4652180 A2 EP4652180 A2 EP 4652180A2
Authority
EP
European Patent Office
Prior art keywords
pen
thp
aef
2nal
7mew
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24706605.3A
Other languages
German (de)
French (fr)
Inventor
Stephanie A. Barros
Santhosh Francis Neelamkavil
Chengzao Sun
Charles HENDRICK
Raymond J. Patch
Sandeep Somani
Jing Zhang
Elisabetta Bianchi
Danila Branca
Roberto COSTANTE
Willy COSTANTINI
Raffaele Ingenito
Martina LOLLOBRIGIDA
Antonia RINALDI
Ashok Bhandari
Gregory Thomas Bourne
Brian Troy FREDERICK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Protagonist Therapeutics Inc
Original Assignee
Janssen Pharmaceutica NV
Protagonist Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica NV, Protagonist Therapeutics Inc filed Critical Janssen Pharmaceutica NV
Publication of EP4652180A2 publication Critical patent/EP4652180A2/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the interleukin-23 (IL-23) cytokine is a heterodimer composed of a unique p19 subunit and the p40 subunit shared with IL-12, which is a cytokine involved in the development of interferon- ⁇ (IFN- ⁇ )-producing T helper 1 (TH1) cells.
  • IFN- ⁇ interferon- ⁇
  • IL-23 and IL-12 both contain the p40 subunit, they have different phenotypic properties.
  • animals deficient in IL- 12 are susceptible to inflammatory autoimmune diseases, whereas IL-23 deficient animals are resistant to these diseases, presumably due to a reduced number of CD4 + T cells producing IL-6, IL-17, and TNF in the CNS of IL-23-deficient animals.
  • IL-23 has been implicated as playing a crucial role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn’s disease.
  • IBDs inflammatory bowel diseases
  • IL-23R is expressed on various adaptive and innate immune cells including Th17 cells, ⁇ T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are found abundantly in the intestine.
  • IL-23R At the intestine mucosal surface, the gene expression and protein levels of IL-23R are found to be elevated in IBD patients. It is believed that IL-23 mediates this effect by promoting the development of a pathogenic CD4 + T cell population that produces IL-6, IL-17, and tumor necrosis factor (TNF). Accordingly, there remains a need for compositions that bind IL-23R to inhibit IL-23 binding and signaling in a patient.
  • IL-23R interleukin-23 receptor
  • pharmaceutical compositions and methods and/or uses of the IL-23R inhibitors for the treatment of inflammatory diseases, autoimmune diseases, and/or related disorders.
  • the present disclosure provides a peptide of Formula (II), comprising the amino acid sequence: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (II), or a pharmaceutically acceptable salt thereof, wherein R 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , R 2 are defined herein.
  • a peptide of Formula (I), comprising the amino acid sequence: X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 - X 12 -X 13 -X 14 - X 15 -X 16 (I),” means that in addition to amino acids X3 through X16, the peptide may include but is not limited to additional amino acids attached to the N-terminus , additional amino acids attached to the C-terminus, N-terminal or C-terminal capping groups, chemical or biological moieties (including but not limited to, for example, lipophilic substituents, antibodies, imaging agents, etc.) conjugated to the peptide at any location, and the like.
  • peptide “comprising,” “include(s),” “having,” “has,” “can,” or “contain(s),” can include embodiments encompassed by the term “consisting essentially of” or “consisting of.”
  • peptide “polypeptide,” and “protein” are used interchangeably herein and typically refer to a molecule comprising a chain of two or more amino acids (e.g., L-amino acids, D-amino acids, modified amino acids, amino acid analogs, amino acid mimetics, etc.).
  • naturally-occurring L-amino acids and D-amino acids are both represented by either conventional three-letter, or capitalized one-letter, amino acid designations of Table 1.
  • naturally-occurring L-amino acids are represented by either conventional three-letter, or capitalized one-letter, amino acid designations of Table 1.
  • D-amino acids are represented by lower-case one-letter amino acid designations corresponding to one-letter designations of Table 1, i.e., g, a, l, m, f, w, k, q, e, s, p, v, i, c, y, h, r, n, d, and t.
  • D-amino acids in the D isomeric form can be substituted for any L-amino acid residue, as long as the desired function is retained by the peptide.
  • D-amino acids may be indicated as customary in lower case when referred to using single-letter abbreviations.
  • D-arginine can be represented as “arg” or “r.”
  • a lower case “d” in front of an amino acid can be used to indicate that it is of the D isomeric form, for example D-lysine can be represented by dK.
  • Amino acids of the D-isomeric form may be located at any of the positions in the IL- 23R inhibitors set forth herein (e.g., any of X3-X16 appearing in the molecule). In some embodiments, amino acids of the D-isomeric form may be located only at any one or more of X3, X5, X6, X8, X13, and optionally one additional position. In other embodiments, amino acids of the D-isomeric form may be located only at any one or more of X3, X8, X13, and optionally one additional position. In other embodiments, amino acids of the D-isomeric form may be located only at any one or more of X8, X13, and optionally one additional position.
  • amino acids of the D-isomeric form may be located only at X3 and optionally one additional position. In other embodiments, amino acids of the D-isomeric form may be located only at X3, and optionally two or three additional positions. In other embodiments, amino acids of the D-isomeric form may be located at only one or two of positions X3 to X16 appearing in the IL-23R inhibitors set forth herein. In other embodiments, amino acids of the D-isomeric form may be located at only three or four of positions X 3 to X 16 appearing in the IL-23R inhibitors set forth herein.
  • an IL-23R inhibitor set forth herein having only positions X 3 to X 15 present may have amino acids of the D-form present in three or four of those positions.
  • amino acids of the D-isomeric form may be located at only five or six of positions X 3 to X 16 appearing in the IL-23R inhibitors set forth herein.
  • Peptides may be naturally occurring, synthetically produced, or recombinantly expressed. Peptides may also comprise additional groups modifying the amino acid chain, for example, functional groups added via post-translational modification.
  • post-translation modifications include, but are not limited to, acetylation, alkylation (including, methylation), biotinylation, glutamylation, glycylation, glycosylation, isoprenylation, lipoylation, phosphopantetheinylation, phosphorylation, selenation, and C-terminal amidation.
  • the term peptide also includes peptides comprising modifications of the amino terminus and/or the carboxy terminus. Modifications of the terminal amino group include, but are not limited to, des- amino, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications.
  • Modifications of the terminal carboxy group include, but are not limited to, amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications (e.g., wherein lower alkyl is C1-C4 alkyl).
  • the term peptide also includes modifications, such as but not limited to those described above, of amino acids falling between the amino and carboxy termini. As is clear to the skilled artisan, the peptide sequences disclosed herein are shown proceeding from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the C-terminus of the peptide.
  • sequences disclosed herein are sequences incorporating either an “-OH” moiety or an “-NH 2 ” moiety at the carboxy terminus (C-terminus) of the sequence.
  • an “-OH” or an “-NH 2 ” moiety at the C-terminus of the sequence indicates a hydroxy group or an amino group, corresponding to the presence of a carboxylic acid (COOH) or an amido (CONH 2 ) group at the C-terminus, respectively.
  • a C-terminal “-OH” moiety may be substituted for a C-terminal “-NH2” moiety, and vice-versa.
  • amino acid refers to an amino acid, a modified amino acid, an amino acid analog, or an amino acid mimetic that is incorporated into a peptide by an amide bond or an amide bond mimetic.
  • aminoacyl residues used herein follow the naming conventions suggested by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature as set out in “Nomenclature of ⁇ -Amino Acids (Recommendations, 1974)” Biochemistry, 14(2), (1975).
  • amino acids and aminoacyl residues employed in this specification and appended claims differ from those suggestions, they will be made clear to the reader.
  • sequences of amino acids that represent IL-23 inhibitors the individual amino acids are separated by a hyphen “-” or brackets e.g, lysine is shown as [K].
  • a hyphen “-” or brackets e.g, lysine is shown as [K].
  • amino acids and other chemical moieties are modified when bound to another molecule.
  • an amino acid side chain may be modified when it forms an intramolecular bridge with another amino acid side chain, e.g., one or more hydrogens may be removed or replaced by the bond.
  • terapéuticaally effective amount means that amount of active peptide or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes preventing, treating or ameliorating the symptoms of a syndrome, disorder or disease being treated.
  • pharmaceutically acceptable means approved or approvable by a regulatory agency of Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmcopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • compositions or pharmaceutical compositions as used herein is intended to encompass a product comprising the specified active pharmaceutical ingredient (API) (i.e., a peptide of the present disclosure), which may include pharmaceutically acceptable excipients, carriers or diluents as described herein, such as in specified amounts defined throughout the disclosure.
  • API active pharmaceutical ingredient
  • compositions or pharmaceutical compositions of the present disclosure may be in different pharmaceutically acceptable forms, which may include, but are not limited to a liquid composition, a tablet or matrix composition, a capsule composition, etc..
  • the composition is a tablet composition
  • the tablet may include, but is not limited to different layers two or more different phases, including an internal phase and an external phase that can comprise a core.
  • the tablet composition can also include, but is not limited to one or more coatings.
  • pharmaceutically acceptable salts and tautomeric forms of the peptides described herein are intended to mean a salt of a free acid or base of peptides represented by Formula (I) that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. It should possess the desired pharmacological activity of the parent compound. See, generally, G.S. Paulekuhn, et al., “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665–72, S.M.
  • a peptide of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • the IL-23R inhibitors of the present disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms of the IL-23R inhibitors of the present disclosure.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • Stereoisomers include enantiomers and diastereomers.
  • the compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other.
  • a “racemic” mixture is a 1:1 mixture of a pair of enantiomers.
  • a “scalemic” mixture of enantiomers is mixture of enantiomers at a ratio other than 1:1.
  • administering with respect to the methods of the present disclosure, means a method for therapeutically or prophylactically preventing, treating or ameliorating a syndrome, disorder or disease as described herein by using a compound of the disclosure, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof.
  • Such methods include administering a therapeutically effective amount of a peptide of the disclosure, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof, at different times during the course of a therapy or concurrently or sequentially as a combination therapy.
  • “Patient” or “subject”, which are used interchangably, refer to a living organism, preferably a mammal, most preferably a human, whom will be or has been treated by a method according to an embodiment of the application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, etc., more preferably a human.
  • NRPs non-human primates
  • treatment is defined as the application or administration of a therapeutic agent, i.e., a compound of the present disclosure (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disorder or disease as described herein, a symptom thereof; or the potential to develop such disorder or disease, where the purpose of the application or administration is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder or disease, its symptoms, or the potential to develop said disorder or disease.
  • Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.
  • the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly or conventionally understood by one of ordinary skill in the art. In the chemical arts a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. A dashed line indicates an optional bond.
  • C 1-6 alkyl and “C 1 -C 6 alkyl” both indicate that the alkyl group has from 1 to 6 carbon atoms.
  • any element, in particular when mentioned in relation to a peptide of the disclosure, or pharmaceutically acceptable salt thereof, shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • a reference to hydrogen includes within its scope 1 H, 2 H (i.e., deuterium or D), and 3 H (i.e., tritium or T).
  • the compounds described herein include a 2 H (i.e., deuterium) isotope.
  • the group denoted -C(1-6)alkyl includes not only -CH 3 , but also CD 3 ; not only CH 2 CH 3 , but also CD 2 CD 3 , etc.
  • references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 15 O and 16 O and 17 O and 18 O.
  • the isotopes may be radioactive or non-radioactive.
  • Radiolabelled compounds of the disclsoure may include a radioactive isotope selected from the group comprising 3 H, 11 C, 18 F, 35 S, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the radioactive isotope is selected from the group of 3 H, 11 C and 18 F.
  • Abbreviation, “(V/V)” refers to the phrase “volume for volume”, i.e., the proportion of a particular substance within a mixture, as measured by volume or a volume amount of a component of the composition disclosed herein relative to the total volume amount of the composition. Accordingly, the quantity is unit less and represents a volume percentage amount of a component relative to the total volume of the composition.
  • a 2% (V/V) solvent mixture can indicate 2 mL of one solvent is present in 100 mL of the solvent mixture.
  • Systemic routes of administration refer to or are defined as a route of administration of drug, a pharmaceutical composition or formulation, or other substance into the circulatory system so that various body tissues and organs are exposed to the drug, formulation or other substance.
  • administration can take place orally (where drug or oral preparations are taken by mouth, and absorbed via the gastrointestinal tract), via enteral administration (absorption of the drug also occurs through the gastrointestinal tract) or parenteral administration (generally injection, infusion, or implantation, etc.
  • Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. Bioavailability of a drug could be impacted by the factors such as properties of the dosage form and properties of the drug.
  • “Digestive tract tissue” as used herein refers to all the tissues that comprise the organs of the alimentary canal. For example only, and without limitation, “digestive tract tissue” includes tissues of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus.
  • Compounds The present disclosure provides a peptide inhibitor of interleukin-23 receptor.
  • the present disclosure provides a peptide of Formula (I), comprising the amino acid sequence: X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 (I), or a pharmaceutically acceptable salt thereof, wherein: X 3 -X 4 -X 5 -X 6 is selected from the group consisting of: X 4 –N–T, dR–X4–N–T, X4–dN–aMeT, X 4 –N–aMeT, dA–dN–dT, X 4 –b3hN–T, X4–N–b3hT, dE–X4–N–T, dR–X 4 –A–A, dR–X4–A–T, dR–X4–dN–dT, dR–X 4 –dN–T, d
  • the present disclosure provides a peptide of Formula (I), comprising the amino acid sequence: X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 (I), or a pharmaceutically acceptable salt thereof, wherein: X 3 -X 4 -X 5 -X 6 is selected from the group consisting of: X 4 –N–T, dR–X4–N–T, X 4 –dN–aMeT, X 4 –N–aMeT, dA–dN–dT, X4–b3hN–T, X 4 –N–b3hT, dE–X 4 –N–T, dR–X4–A–A, dR–X 4 –A–T, dR–X 4 –dN–dT, dR–X4–dN–dT
  • X 3 -X 4 -X 5 -X 6 is Abu–N–T
  • X3-X4-X5-X6 is aMeC–N–T
  • X 3 -X 4 -X 5 -X 6 is C–N–T
  • X 3 -X 4 -X 5 -X 6 is Pen–N–T
  • X3-X4-X5-X6 is dR–Abu–N–T
  • X3-X4-X5-X6 is dR–aMeC–N–T
  • X 3 -X 4 -X 5 -X 6 is dR–C–N–T
  • X 3 -X 4 -X 5 -X 6 is dR–Pen–N–T
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP
  • X3-X4-X5-X6 is X4–N–T
  • X3-X4-X5-X6 is dR–X4–N–T
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–X 9 –AEF–2Nal–THP
  • X 13 -X 14 -X 15 -X 16 is E–N–3Pya–Sar
  • X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar.
  • X 3 -X 4 -X 5 -X 6 is X 4 –N–T
  • X3-X4-X5-X6 is aMeC–N–T
  • X 3 -X 4 -X 5 -X 6 is C–N–T
  • X 3 -X 4 -X 5 -X 6 is Pen–N–T
  • X3-X4-X5-X6 is dR–Abu–N–T
  • X 3 -X 4 -X 5 -X 6 is dR–aMeC–N–T
  • X3-X4-X5-X6 is dR–C–N–T
  • X3-X4-X5-X6 is dR–Pen–N–T
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP
  • X 3 -X 4 -X 5 -X 6 is X 4 –N–T
  • X 3 -X 4 -X 5 -X 6 is dR–X 4 –N–T
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–THP
  • X 13 -X 14 -X 15 -X 16 is E–N–3Pya–Sar
  • X 13 -X 14 -X 15 -X 16 is K(Ac)–N–3Pya–Sar.
  • X4 is 4AminoPro, Abu, aG, aMeC, Api, C, D, Dap, Dab, E, hA, hE, hK, K, Orn, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), Pra, R5H, R5Me, S5H, or S5Me.
  • X 4 is Dap, Dab, hK, K, or Orn.
  • X 4 is Api, D, E, or hE.
  • X 4 is aG, R5H, R5Me, S5H, or S5Me.
  • X4 is 4AminoPro, aG, Dap, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra.
  • X 4 is Abu, aMeC, C, Pen, Pen(oXyl), Pen(mXyl), or Pen(pXyl).
  • X 4 is Abu, aMeC, C, or Pen.
  • X 4 is Abu, C, or Pen.
  • X4 is Abu or Pen.
  • X 4 is 4AminoPro.
  • X 4 is 4RAminoPro.
  • X 4 is 4SAminoPro.
  • X 4 is Abu. In some embodiments, X4 is aG. In some embodiments, X4 is aMeC. In some embodiments, X4 is Api. In some embodiments, X4 is C. In some embodiments, X4 is D. In some embodiments, X4 is Dap. In some embodiments, X 4 is Dab. In some embodiments, X 4 is E. In some embodiments, X 4 is hA. In some embodiments, X 4 is hE. In some embodiments, X 4 is hK. In some embodiments, X 4 is K. In some embodiments, X4 is Orn. In some embodiments, X4 is Pen.
  • X 4 is Pen(oXyl). In some embodiments, X 4 is Pen(mXyl). In some embodiments, X 4 is Pen(pXyl). In some embodiments, X 4 is Pra. In some embodiments, X 4 is R5H. In some embodiments, X4 is R5Me. In some embodiments, X4 is S5H. In some embodiments, X4 isS5Me. In some embodiments, X 9 is aMeC, aG, Api, C, D, Dab, Dap, E, hA, hE, hK, K, Orn, Pen, Dap(N3), R5H, R5Me, S5H, or S5Me.
  • X9 is Dap, Dab, hK, K, or Orn. In some embodiments, X 9 is Api, D, E, or hE. In some embodiments, X 9 is aG, R5H, R5Me, S5H, or S5Me. In some embodiments, X9 is aG, D, E, hE, or Dap(N3). In some embodiments, X9 is aMeC, C, or Pen. In some embodiments, X 9 is aMeC or Pen. In some embodiments, X9 is aMeC. In some embodiments, X9 is aG. In some embodiments, X9 is Api.
  • X9 is C. In some embodiments, X9 is D. In some embodiments, X 9 is Dab. In some embodiments, X 9 is Dap. In some embodiments, X 9 is E. In some embodiments, X 9 is hA. In some embodiments, X 9 is hE. In some embodiments, X 9 is hK. In some embodiments, X9 is K. In some embodiments, X9 is Orn. In some embodiments, X9 is Pen. In some embodiments, X 9 is Dap(N3). In some embodiments, X 9 is R5H. In some embodiments, X 9 is R5Me. In some embodiments, X 9 is S5H.
  • X 9 is S5Me.
  • X 4 is Abu, aMeC, C, or Pen, and X 9 is aMeC, C, or Pen.
  • X 4 is Abu and X 9 is C.
  • X 4 is Abu and X 9 is aMeC.
  • X4 is Abu and X9 is Pen.
  • X4 is C and X9 is C.
  • X4 is C and X9 is aMeC.
  • X 4 is C and X 9 is Pen.
  • X 4 is Pen and X 9 is C.
  • X 4 is Pen and X 9 is aMeC. In some embodiments, X4 is Pen and X9 is Pen. In some embodiments, X 4 is aMeC and X 9 is C. In some embodiments, X 4 is aMeC and X 9 is aMeC. In some embodiments, X 4 is aMeC and X 9 is Pen. In some embodiments, X4 is Pen(oXyl) and X9 is C. In some embodiments, X4 is Pen(oXyl) and X 9 is aMeC. In some embodiments, X 4 is Pen(oXyl) and X 9 is Pen.
  • X 4 is Pen(mXyl) and X 9 is C. In some embodiments, X 4 is Pen(mXyl) and X9 is aMeC. In some embodiments, X4 is Pen(mXyl) and X9 is Pen. In some embodiments, X4 is Pen(pXyl) and X9 is C. In some embodiments, X4 is Pen(pXyl) and X 9 is aMeC. In some embodiments, X 4 is Pen(pXyl) and X 9 is Pen. In some embodiments, X 4 is 4AminoPro and X 9 is D. In some embodiments, X 4 is 4AminoPro and X9 is E.
  • X4 is 4AminoPro and X9 is hE.
  • X 4 Dap, Dab, hK, K, or Orn and X 9 is Api, D, E, or hE.
  • X 4 is Dap and X 9 is Api, D, E, or hE.
  • X 4 is Dab and X 9 is Api, D, E, or hE.
  • X4 is hK and X9 is Api, D, E, or hE.
  • X 4 is K and X 9 is Api, D, E, or hE.
  • X 4 is Orn and X 9 is Api, D, E, or hE.
  • X 4 Dap, Dab, hK, K, or Orn and X 9 is Api.
  • X 4 Dap, Dab, hK, K, or Orn, and X 9 is D.
  • X 4 Dap, Dab, hK, K, or Orn and X9 is E.
  • X4 Dap, Dab, hK, K, or Orn, and X9 is hE.
  • X4 is Api, D, E, or hE and X9 is Dap, Dab, hK, K, or Orn.
  • X 4 is Api and X 9 is Dap, Dab, hK, K, or Orn.
  • X 4 is D and X9 is Dap, Dab, hK, K, or Orn.
  • X4 is E and X9 is Dap, Dab, hK, K, or Orn.
  • X4 is hE and X9 is Dap, Dab, hK, K, or Orn.
  • X 4 is Api, D, E, or hE and X 9 is Dap. In some embodiments, X 4 is Api, D, E, or hE and X 9 is Dab. In some embodiments, X 4 is Api, D, E, or hE and X 9 is hK. In some embodiments, X 4 is Api, D, E, or hE and X9 is K. In some embodiments, X4 is Api, D, E, or hE and X9 is Orn. In some embodiments, X 4 is Dap and X 9 is D. In some embodiments, X 4 is Dap and X 9 is E.
  • X 4 is Dap and X 9 is hE.
  • X4 is aG, R5H, R5Me, S5H, or S5Me and X9 is aG, R5H, R5Me, S5H, or S5Me.
  • X 4 is R5H, R5Me, S5H, or S5Me and X 9 is R5H, R5Me, S5H, or S5Me.
  • X4 is Pra and X9 is Dap(N3).
  • X4 is aG and X9 is aG.
  • X4 is hA and X9 is hA.
  • the peptide comprises a linker between the ⁇ -carbon of X 4 and the ⁇ -carbon of X 9 .
  • the linker is less than 24 Angstroms ( ⁇ ) in length. In some embodiments, the linker is less than 20 ⁇ in length. In some embodiments, the linker is between 4 ⁇ and 24 ⁇ in length. In some embodiments, the linker is between 4 ⁇ and 20 ⁇ in length. In some embodiments, the linker is between 10 ⁇ and 24 ⁇ in length.
  • the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 18 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 2 and 16 carbon atoms. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 16 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, S, and H atoms, and comprises between 4 and 16 atoms selected from C and S.
  • the linker consists of C, N, S, O, and H atoms, and comprises between 2 and 14 carbon atoms. In some embodiments, the linker consists of C, S, and H atoms, and comprises between 2 and 14 carbon atoms. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 14 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 12 atoms selected from C, N, S, and O.
  • the linker consists of C, N, S, O, and H atoms, and comprises between 2 and 12 carbon atoms.
  • the peptide is cyclized via a linkage between two amino acid residues (e.g., at X4 and X9) having a structure selected from the following:
  • the peptide is cyclized via a linkage between two amino acid residues (e.g., at X4 and X9) having a structure selected from the following:
  • the peptide is cyclized via a linkage between the residues at X4
  • the peptide is cyclized via a linkage between the residues at X 4 In some embodiments, the peptide is cyclized via a linkage between the residues at X 4 and X 9 having a structure selected from the following:
  • the peptide is cyclized via a linkage between the residues at X4 and X 9 having a structure selected from the following: In some embodiments, the peptide is cyclized via a linkage between the residues at X4 and X 9 having the following structure: Pen – Pen.
  • the present disclosure provides a peptide of Formula (I), comprising the amino acid sequence: X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 (I), or a pharmaceutically acceptable salt thereof, wherein: X3-X4-X5-X6 is selected from the group consisting of: Abu–N–T, C–N–T, Pen–N–T, dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, Pen–N–b3hT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dR–dR
  • the peptide comprises an amino acid sequence selected from the group consisting of: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I-A1), X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (I-A2), and R 1 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (I-A3), or a pharmaceutically acceptable salt thereof.
  • R 1 represents the N-terminal end of the peptide, which may be, for example, a hydrogen or a chemical moiety or functional group substituted on the amino group (e.g., an acetate group).
  • R2 represents the carboxyl end, which may be, for example the OH of the carboxyl or a chemical moiety or functional group attached thereto or substituted for the OH group (e.g., an amino group to give a terminal amide, e.g., -CONH 2 );
  • R1 is MeCO or EtCO
  • R2 is CONH2.
  • the peptide comprises an amino acid sequence of Formula (I-A1): R 1 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 (I-A1), or a pharmaceutically acceptable salt thereof, wherein R 1 is MeCO or EtCO.
  • the peptide comprises an amino acid sequence of Formula (I-A2): X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (I-A2), or a pharmaceutically acceptable salt thereof, wherein R 2 is CONH2.
  • the peptide comprises an amino acid sequence of Formula (I-A3): R 1 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (I-A3), or a pharmaceutically acceptable salt thereof, wherein R 1 is MeCO or EtCO, and R 2 is CONH2.
  • X3-X4-X5-X6 is Abu–N–T
  • X 3 -X 4 -X 5 -X 6 is C–N–T
  • X 3 -X 4 -X 5 -X 6 is Pen–N–T
  • X3-X4-X5-X6 is dR–Abu–N–T
  • X 3 -X 4 -X 5 -X 6 is dR–C–N–T
  • X 3 -X 4 -X 5 -X 6 is dR–Pen–N–T
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP
  • X3-X4-X5-X6 is X4–dN–aMeT, X4–N–aMeT, dA–dN–dT, X4– b3hN–T, X4–N–b3hT, dE–X4–N–T, dR–X4–A–A, dR–X4–A–T, dR–X4–dN–dT, dR–X4–dN–T, dR–X 4 –N–A, dR–X 4 –N–dT, or R–X 4 –N–T.
  • X3-X4-X5-X6 is Abu–N–T, C–N–T, dR–Abu–N–T, dR–C–N–T, Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, Pen–N–b3hT, dE–Pen–N–T, dR– Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR–Pen–dN–T, dR–Pen–N–A, dR–Pen–N–dT, or R– Pen–N–T.
  • X3-X4-X5-X6 is Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, Pen–N–b3hT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR– Pen–dN–T, dR–Pen–N–A, dR–Pen–N–dT, or R–Pen–N–T.
  • X3-X4-X5-X6 is X4–N–T, dR–X4–N–T, X4–dN–aMeT, X4–N– aMeT, dA–dN–dT, X 4 –b3hN–T, X 4 –N–b3hT, dE–X 4 –N–T, dR–X 4 –A–A, dR–X 4 –A–T, or dR– X 4 –N–A.
  • X3-X4-X5-X6 is Abu–N–T, C–N–T, Pen–N–T, dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, Pen–N– b3hT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, or dR–Pen–N–A.
  • X 3 -X 4 -X 5 -X 6 is X 4 –N–T, X 4 –dN–aMeT, X 4 –N–aMeT, dA–dN– dT, X4–b3hN–T, or X4–N–b3hT.
  • X 3 -X 4 -X 5 -X 6 is Abu–N–T, C–N–T, Pen–N–T, Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, or Pen–N–b3hT.
  • X3-X4-X5-X6 is dR–X4–N–T, dA–dN–dT, dE–X4–N–T, dR–X4– A–A, dR–X 4 –A–T, dR–X 4 –dN–dT, dR–X 4 –dN–T, dR–X 4 –N–A dR–X 4 –N–dT, or R–X 4 –N–T.
  • X 3 -X 4 -X 5 -X 6 is dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, dA– dN–dT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR–Pen–dN–T, dR–Pen– N–A, dR–Pen–N–dT, and R–Pen–N–T.
  • X 3 -X 4 -X 5 -X 6 is Pen–N–T, dR–Pen–N–T, Pen–b3hN–T, Pen–N– b3hT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR–Pen–dN–T, dR–Pen– N–A, dR–Pen–N–dT, and R–Pen–N–T.
  • X 3 -X 4 -X 5 -X 6 is Abu–N–T, C–N–T, dR–Abu–N–T, dR–C–N–T, Abu–dN–aMeT, Abu–N–aMeT, and dA–dN–dT.
  • X3-X4-X5-X6 is X4–N–T, dR–X4–N–T, X4–N–aMeT, X4–N– b3hT, dE–X 4 –N–T, dR–X 4 –N–A, dR–X 4 –N–dT, or R–X 4 –N–T.
  • X 3 -X 4 -X 5 -X 6 is Abu–N–T, C–N–T, Pen–N–T, dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, Abu–N–aMeT, Pen–N–b3hT, dE–Pen–N–T, dR–Pen–N–A, dR– Pen–N–dT, or R–Pen–N–T.
  • X 3 -X 4 -X 5 -X 6 is X 4 –dN–aMeT, dA–dN–dT, X 4 –b3hN–T, dR–X 4 – A–A, dR–X4–A–T, dR–X4–dN–dT, or dR–X4–dN–T.
  • X3-X4-X5-X6 is Abu–dN–aMeT, dA–dN–dT, Pen–b3hN–T, dR– Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, or dR–Pen–dN–T.
  • X 3 -X 4 -X 5 -X 6 is X 4 –N–T, dR–X 4 –N–T, X 4 –b3hN–T, dE–X 4 –N–T, dR–X4–A–T, dR–X4–dN–T, or R–X4–N–T.
  • X 3 -X 4 -X 5 -X 6 is Abu–N–T, C–N–T, Pen–N–T, dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, Pen–b3hN–T, dE–Pen–N–T, dR–Pen–A–T, dR–Pen–dN–T, or R– Pen–N–T.
  • X 3 -X 4 -X 5 -X 6 is X 4 –dN–aMeT, X 4 –N–aMeT, dA–dN–dT, X 4 –N– b3hT, dR–X 4 –A–A, dR–X 4 –dN–dT, dR–X 4 –N–A, or dR–X 4 –N–dT.
  • X3-X4-X5-X6 is Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–N–b3hT, dR–Pen–A–A, dR–Pen–dN–dT, dR–Pen–N–A, or dR–Pen–N–dT.
  • X 3 -X 4 -X 5 -X 6 is X 4 –N–T.
  • X 3 -X 4 -X 5 -X 6 is dR–X 4 –N–T.
  • X 3 -X 4 -X 5 -X 6 is X 4 –dN–aMeT. In some embodiments, X 3 - X4-X5-X6 is X4–N–aMeT. In some embodiments, X3-X4-X5-X6 is dA–dN–dT. In some embodiments, X 3 -X 4 -X 5 -X 6 is X 4 –b3hN–T. In some embodiments, X 3 -X 4 -X 5 -X 6 is X 4 –N–b3hT. In some embodiments, X 3 -X 4 -X 5 -X 6 is dE–X 4 –N–T.
  • X 3 -X 4 -X 5 -X 6 is dR– X4–A–A. In some embodiments, X3-X4-X5-X6 is dR–X4–A–T. In some embodiments, X3-X4-X5- X 6 is dR–X 4 –dN–dT. In some embodiments, X 3 -X 4 -X 5 -X 6 is dR–X 4 –dN–T. In some embodiments, X 3 -X 4 -X 5 -X 6 is dR–X 4 –N–A.
  • X 3 -X 4 -X 5 -X 6 is dR–X 4 –N– dT,. In some embodiments, X3-X4-X5-X6 is R–X4–N–T. In some embodiments, X3-X4-X5-X6 is Abu–N–T. In some embodiments, X3-X4-X5-X6 is C–N–T. In some embodiments, X 3 -X 4 -X 5 -X 6 is Pen–N–T. In some embodiments, X 3 -X 4 -X 5 -X 6 is dR–Abu–N–T.
  • X 3 -X 4 -X 5 -X 6 is dR–C–N–T. In some embodiments, X 3 - X4-X5-X6 is dR–Pen–N–T. In some embodiments, X3-X4-X5-X6 is Abu–dN–aMeT. In some embodiments, X 3 -X 4 -X 5 -X 6 is Abu–N–aMeT. In some embodiments, X 3 -X 4 -X 5 -X 6 is dA–dN– dT. In some embodiments, X 3 -X 4 -X 5 -X 6 is Pen–b3hN–T.
  • X 3 -X 4 -X 5 -X 6 is Pen–N–b3hT. In some embodiments, X3-X4-X5-X6 is dE–Pen–N–T. In some embodiments, X3- X 4 -X 5 -X 6 is dR–Pen–A–A. In some embodiments, X 3 -X 4 -X 5 -X 6 is dR–Pen–A–T. In some embodiments, X 3 -X 4 -X 5 -X 6 is dR–Pen–dN–dT. In some embodiments, X 3 -X 4 -X 5 -X 6 is dR–Pen– dN–T.
  • X 3 -X 4 -X 5 -X 6 is dR–Pen–N–A. In some embodiments, X 3 -X 4 -X 5 - X6 is dR–Pen–N–dT. In some embodiments, X3-X4-X5-X6 is R–Pen–N–T.
  • X7-X8-X9-X10-X11-X12 is 7(3(1NMepip)pyraz)W–K(Ac)–X9– AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X 9 –AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X 9 – AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X9– AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X9–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W– K(Ac)–X 9 –AEF–2Nal–THP, 7
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal– THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF– 2Nal–THP, 7(3NpyrlonePh)W–K(A
  • X7-X8-X9-X10-X11-X12 is 7(3(1NMepip)pyraz)W–K(Ac)–Pen– AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)– aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W– K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–THP, 7MeW–A–X9–A–2Nal–THP, 7MeW–A–X9–AEF(G)–2Nal–THP, 7MeW–A–X9–AEF–2Nal– THP, 7MeW–b3hK–X 9 –AEF–2Nal–THP, 7MeW–b3hQ–X 9 –AEF–2Nal–THP, 7MeW–b3hQ– X 9 –AEF–b3hF–THP, 7MeW–dK(Ac)–X 9 –AEF–2Nal–THP, 7MeW–K(Ac)–X 9 –A–2Nal–THP, 7MeW–K(Ac)–X9–A–A–THP, 7MeW
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen—AEF–2Nal–THP, 7MeW–A–Pen–A– 2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW– b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF– b3hF–THP, 7MeW–dK(Ac)–aMeC–AEF, 7Me
  • X7-X8-X9-X10-X11-X12 is 7(3(1NMepip)pyraz)W–K(Ac)–X9– AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X 9 –AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X 9 – AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X 9 –AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X 9 – AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X9–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W– K(Ac)–X 9 –AEF–2N
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7(3(1NMepip)pyraz)W–K(Ac)–Pen– AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)– aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W– K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–AEF–
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–X 9 –AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–X9–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X9–AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–X 9 –AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X 9 –AEF(G)– 2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X 9 –AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X 9 –AEF– 2Nal–THP, 7(5(
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–A–X 9 –A–2Nal–THP, 7MeW– A–X9–AEF(G)–2Nal–THP, 7MeW–A–X9–AEF–2Nal–THP, 7MeW–b3hK–X9–AEF–2Nal– THP, 7MeW–b3hQ–X 9 –AEF–2Nal–THP, 7MeW–b3hQ–X 9 –AEF–b3hF–THP, 7MeW– dK(Ac)–X 9 –AEF–2Nal–THP, A–A–X 9 –A–A–THP, A–A–X 9 –AEF–2Nal–THP, or d7MeW– dK(Ac)–dA–dY–d2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–A–Pen–A–2Nal–THP, 7MeW– A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal– THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW– dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, A–A–Pen–A–A–THP, A–A–Pen–AEF–2Nal–THP, or d7MeW–dK
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen– AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W– K(Ac)–Pen–AEF–2Nal–THP, 7(6(2
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW– dK(Ac)–aMeC–AEF–2Nal–THP, or d7MeW–dK(Ac)–dA–dY–d2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–X 9 –AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–X9–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X9–AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X9–AEF– 2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X 9 –AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)– X 9 –AEF–2Nal–THP
  • 7MeW–K(Ac)–aMeC–AEF–2Nal–THP 7MeW–K(Ac)–C–AEF– 2Nal–THP
  • 7MeW–K(Ac)–Pen—AEF–2Nal–THP 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF– 2Nal–THP
  • 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP 7(3NAcPh)W–K(Ac)–aMeC— AEF–2Nal–THP
  • 7(3NpyrlonePh)W–K(Ac)– Pen–AEF–2Nal–THP 7(5(2(4OMePh)Pyr
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7(3NAcPh)W–K(Ac)–X 9 –AEF(G)– 2Nal–THP, 7MeW–A–X9–A–2Nal–THP, 7MeW–A–X9–AEF(G)–2Nal–THP, 7MeW–K(Ac)– X 9 –A–2Nal–THP, 7MeW–K(Ac)–X 9 –A–A–THP, 7MeW–K(Ac)–X 9 –APF–2Nal–THP, 7MeW– K(Ac)–X 9 –b3hY–2Nal–THP, 7MeW–K(Ac)–X 9 –F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–X 9 – F(4TzlAme2)
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7(3NAcPh)W–K(Ac)–Pen–AEF(G)– 2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–K(Ac)– Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW– K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7M
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–X 9 –AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–X 9 –AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X 9 –AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF(G)– 2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X 9 –AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X 9 –AEF– 2Nal–THP, 7(5(
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen– AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–b3hQ–X 9 –AEF–b3hF–THP, 7MeW–K(Ac)–X 9 –A–A–THP, 7MeW–K(Ac)–X 9 –AEF–b3hF–THP, A–A–X 9 –A–A–THP, A– K(Ac)–X9–AEF–A–THP, b3hW–K(Ac)–X9–AEF–b3hF–THP, d7MeW–dK(Ac)–dA–dY– d2Nal–THP, F–K(Ac)–X 9 –AEF–F–THP, L–K(Ac)–X 9 –AEF–L–THP, 7MeW–K(Ac)–X 9 –AEF– F–THP, or
  • X7-X8-X9-X10-X11-X12 is 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, A–A–Pen–A–A–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, d7MeW–dK(Ac)–dA–dY– d2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen– AEF–F–THP, or 7MeW–K(Ac)–P
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–X 9 –AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X 9 –AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF(G)– 2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X9–AEF– 2Nal–THP, 7(5(2(4OMePh)
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen– AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–A or 7MeW–K(Ac)–X 9 –AEF–2Nal–Aib.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–Pen–AEF–2Nal–A or 7MeW–K(Ac)–Pen–AEF–2Nal–Aib.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–X 9 –AEF–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7(3(1NMepip)pyraz)W–K(Ac)–X 9 –AEF–2Nal– THP.
  • X7-X8-X9-X10-X11-X12 is 7(3(6AzaInd1Me))W–K(Ac)–X9–AEF– 2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7(3NAcPh)W–K(Ac)–X 9 –AEF– 2Nal–THP. In some embodiments, X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7(3NAcPh)W–K(Ac)–X 9 –AEF(G)– 2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3NPyrazPh)W–K(Ac)–X9–AEF– 2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is 7(3NpyrlonePh)W–K(Ac)–X9– AEF–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7(5(2(4OMePh)Pyr))W– K(Ac)–X 9 –AEF–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7(6(2OxdeQuin8Me))W –K(Ac)–X9–AEF–2Nal–THP.
  • X7-X8-X9-X10- X 11 -X 12 is 7(6(2OxIquin))W –K(Ac)–X 9 –AEF–2Nal–THP.
  • X 7 -X 8 -X 9 - X 10 -X 11 -X 12 is 7(7(124TAZP))W–K(Ac)–X 9 –AEF–2Nal–THP.
  • X 7 -X 8 - X9-X10-X11-X12 is 7(7(2OMeQuin))W–K(Ac)–X9–AEF–2Nal–THP.
  • X7- X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–A–X 9 –A–2Nal–THP. In some embodiments, X 7 -X 8 -X 9 -X 10 -X 11 - X 12 is 7MeW–A–X 9 –AEF(G)–2Nal–THP. In some embodiments, X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–A–X9–AEF–2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is 7MeW–b3hK– X9–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–b3hQ–X9–AEF– 2Nal–THP. In some embodiments, X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–b3hQ–X 9 –AEF–b3hF– THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–dK(Ac)–X 9 –AEF–2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–A–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–X 9 –A–A–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–X 9 –AEF–2Nal–A.
  • X 7 -X 8 -X 9 - X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–Aib.
  • X7-X8-X9-X10-X11- X 12 is 7MeW–K(Ac)–X 9 –AEF–b3hF–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–X 9 –APF–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW– K(Ac)–X9–b3hY–2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)– X 9 –F(4TzlAme2)–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)– X9–F(4TzlG2)–2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9– YCF2H–2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is A–A–X9–A–A–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is b3hW– K(Ac)–X 9 –b3hY–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is d7MeW– dK(Ac)–dA–dY–d2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is F–K(Ac)–X9– AEF–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is F–K(Ac)–X 9 –AEF–F–THP. In some embodiments, X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is L–K(Ac)–X 9 –AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is L–K(Ac)–X9–AEF–L–THP.
  • X7- X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–X 9 –AEF–F–THP. In some embodiments, X 7 -X 8 -X 9 -X 10 - X 11 -X 12 is 7MeW–K(Ac)–X 9 –AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–C–AEF–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal– THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal– THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7(3NAcPh)W–K(Ac)–Pen–AEF(G)– 2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is 7(3NPyrazPh)W–K(Ac)–Pen– AEF–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7(3NpyrlonePh)W–K(Ac)– Pen–AEF–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7(5(2(4OMePh)Pyr))W– K(Ac)–Pen–AEF–2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP.
  • X7-X8-X9-X10- X 11 -X 12 is 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP.
  • X 7 -X 8 -X 9 - X 10 -X 11 -X 12 is 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP.
  • X 7 -X 8 - X9-X10-X11-X12 is 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP.
  • X7- X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–A–Pen–A–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 - X 12 is 7MeW–A–Pen–AEF(G)–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–A–Pen–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW– b3hK–Pen–AEF–2Nal–THP. In some embodiments, X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–b3hQ– Pen–AEF–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–b3hQ–Pen– AEF–b3hF–THP.
  • X7-X8-X9-X10-X11-X12 is 7MeW–dK(Ac)–aMeC– AEF–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–dK(Ac)–Pen–AEF– 2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–A–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–A–A–THP. In some embodiments, X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–Pen–AEF–2Nal–A.
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–Aib. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–b3hF–THP. In some embodiments, X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–Pen–APF–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–Pen–b3hY–2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is A–A–Pen–A–A–THP.
  • X7-X8-X9- X 10 -X 11 -X 12 is A–A–Pen–AEF–2Nal–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is A– K(Ac)–Pen–AEF–A–THP.
  • X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is b3hW–K(Ac)–Pen– AEF–2Nal–THP.
  • X7-X8-X9-X10-X11-X12 is b3hW–K(Ac)–Pen–AEF– b3hF–THP.
  • X7-X8-X9-X10-X11-X12 is b3hW–K(Ac)–Pen–b3hY–2Nal– THP.
  • X7- X 8 -X 9 -X 10 -X 11 -X 12 is L–K(Ac)–Pen–AEF–2Nal–THP. In some embodiments, X 7 -X 8 -X 9 -X 10 - X 11 -X 12 is L–K(Ac)–Pen–AEF–L–THP. In some embodiments, X 7 -X 8 -X 9 -X 10 -X 11 -X 12 is 7MeW–K(Ac)–Pen–AEF–F–THP.
  • X7-X8-X9-X10-X11-X12 is 7MeW– K(Ac)–Pen–AEF–L–THP.
  • X 13 -X 14 -X 15 -X 16 is K(Ac)–N–3Pya–Sar, A–N–3Pya–Sar, b3hE– N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya– Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N– L–Sar, K(Ac)–N–5Me
  • X 13 -X 14 -X 15 -X 16 is A–N–3Pya–Sar, b3hE–N–3Pya–Sar, dE–dN– 3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N–L–Sar, K(Ac)–N– 5MePyridinAla–Sar, or R–N–3Pya–Sar.
  • X13-X14-X15-X16 is E–N–3Pya–Sar, K(Ac)–N–3Pya–Sar, A–N– 3Pya–Sar, b3hE–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–F–3Pya– Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N–L–Sar, K(Ac)–N–5MePyridinAla– Sar, or R–N–3Pya–Sar.
  • X 13 -X 14 -X 15 -X 16 is E–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK– bMeDTyr, or E–N–L–Sar.
  • X 13 -X 14 -X 15 -X 16 is K(Ac)–N–3Pya–Sar, A–N–3Pya–Sar, b3hE– N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, K(Ac)–N–5MePyridinAla–Sar, or R–N–3Pya–Sar.
  • X 13 -X 14 -X 15 -X 16 is E–N–3Pya–Sar, K(Ac)–N–3Pya–Sar, A–N– 3Pya–Sar, b3hE–N–3Pya–Sar, dE–N–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK– bMeDTyr, E–N–L–Sar, K(Ac)–N–5MePyridinAla–Sar, or R–N–3Pya–Sar.
  • X 13 -X 14 -X 15 -X 16 is dE–dN–3Pya–Sar, E–A–3Pya–Sar, E–A–A– Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, or E–F–3Pya–Sar.
  • X13-X14-X15-X16 is E–N–3Pya–Sar, K(Ac)–N–3Pya–Sar, A–N– 3Pya–Sar, b3hE–N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–b3hN– 3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, or R–N–3Pya–Sar.
  • X13-X14-X15-X16 is E–A–A–Sar, E–N–A–Sar, E–N–b3hF–Sar, E– N–dK–bMeDTyr, E–N–L–Sar, or K(Ac)–N–5MePyridinAla–Sar.
  • the Abu, C, or Pen in X 3 -X 4 -X 5 -X 6 is linked to aMeC, C, or Pen in X 7 -X 8 -X 9 -X 10 -X 11 -X 12 via a disulfide or thioether bond.
  • the Abu, C, or Pen in X3-X4-X5-X6 is linked to aMeC, C, or Pen in X 7 -X 8 -X 9 -X 10 -X 11 -X 12 via a linkage selected from the following:
  • the Abu, C, or Pen in X 3 -X 4 -X 5 -X 6 is linked to aMeC, C, or Pen in X 7 -X 8 -X 9 -X 10 -X 11 -X 12 via a linkage selected from the following:
  • the present disclosure further provides a peptide having an amino acid sequence according to any one of SEQ ID NOS: 1-89, as shown in Table 2, or a pharmaceutically acceptable salt thereof. Table 2.
  • the present disclosure provides a peptide of Formula (II), comprising the amino acid sequence: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (II), or a pharmaceutically acceptable salt thereof, wherein: R 1 is an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker, or R1 is AEEP or MeCO; X 3 is K or R, or absent, wherein the K is conjugated to a reactive handle, optionally via a linker; X 4 is an amino acid that is optionally linked to the amino acid at X 9 X 5 is N or Q; X6 is 7MeW or T; X7 is 7MeW, T, or W; X 8 is K(Ac) or Q; X 9 is an albumin-
  • the peptide comprises a linker between the ⁇ -carbon of X 4 and the ⁇ -carbon of X 9 .
  • the linker is less than 24 Angstroms ( ⁇ ) in length. In some embodiments, the linker is less than 20 ⁇ in length. In some embodiments, the linker is between 4 ⁇ and 24 ⁇ in length. In some embodiments, the linker is between 4 ⁇ and 20 ⁇ in length. In some embodiments, the linker is between 10 ⁇ and 24 ⁇ in length.
  • the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 18 atoms selected from C, N, S, and O.
  • the linker consists of C, N, S, O, and H atoms, and comprises between 2 and 16 carbon atoms. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 16 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, S, and H atoms, and comprises between 4 and 16 atoms selected from C and S. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 2 and 14 carbon atoms. In some embodiments, the linker consists of C, S, and H atoms, and comprises between 2 and 14 carbon atoms.
  • the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 14 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 12 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 2 and 12 carbon atoms.
  • the present disclosure provides a peptide of Formula (II), comprising the amino acid sequence: R 1 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (II), or a pharmaceutically acceptable salt thereof, wherein: R 1 is an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker, or R1 is AEEP or MeCO; X 3 is K or R, or absent, wherein the K is conjugated to a reactive handle, optionally via a linker; X4 is 4AminoPro, A, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra
  • the present disclosure provides a peptide of Formula (II), comprising the amino acid sequence: R 1 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (II), or a pharmaceutically acceptable salt thereof, wherein: R1 is an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker, or R 1 is AEEP or MeCO; X3 is dK or dR, or absent, wherein the dK is conjugated to a reactive handle, optionally via a linker; X 4 is 4AminoPro, A, Abu, Dap, Pen, or Pra X5 is N or Q; X 6 is 7MeW or T; X 7 is 7MeW
  • the present disclosure provides a peptide of Formula (II-A), comprising the amino acid sequence: R1-X3-X4-N-T-X7-K(Ac)-X9-AEF-2Nal-X12-X13-N-X15-X16-R2 (II-A), or a pharmaceutically acceptable salt thereof, wherein: R 1 is an albumin-binding moiety, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker, or R1 is AEEP or MeCO; X 3 is K or R, or absent, wherein the K is conjugated to a reactive handle, optionally via a linker; X4 is 4AminoPro, A, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra X 7 is 7MeW or W; X9 is
  • the present disclosure provides a peptide of Formula (II-A), comprising the amino acid sequence: R 1 -X 3 -X 4 -N-T-X 7 -K(Ac)-X 9 -AEF-2Nal-X 12 -X 13 -N-X 15 -X 16 -R 2 (II-A), or a pharmaceutically acceptable salt thereof, wherein: R1 is an albumin-binding moiety, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker, or R 1 is AEEP or MeCO; X 3 is dK or dR, or absent, wherein the dK is conjugated to a reactive handle, optionally via a linker; X4 is 4AminoPro, A, Abu, Dap, Pen, or Pra X 7 is 7MeW or W; X9 is A, C, D, Dap, E, hE, or Pen;
  • the peptide contains one, and only one, linkage selected from the group consisting of: a linkage between AEEP at R 1 and E at X 13 ; a linkage between 4AminoPro at X 4 and D, E, or hE at X 9 ; a linkage between Abu at X4 and aMeC, C, or Pen at X9; a linkage between aG at X 4 and aG at X 9 ; a linkage between aMeC at X 4 and aMeC, C, or Pen at X 9 ; a linkage between C at X4 and aMeC, C, or Pen at X9; a linkage between Dap at R 4 and D at R 9 ; a linkage between Pen at R4 and aMeC, C, or Pen at R9; a linkage between Pen(oXyl) at R4 and Pen at R9; a linkage between Pen(mXyl) at R 4
  • R 1 is an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker.
  • R1 is an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle.
  • R 1 is an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, each of which is bound to the rest of the peptide via a linker.
  • R 1 is an albumin-binding moiety optionally bound to the rest of the peptide via a linker.
  • R 1 is biotin optionally bound to the rest of the peptide via a linker. In some embodiments, R1 is an imaging agent optionally bound to the rest of the peptide via a linker. In some embodiments, R1 is a second peptide optionally bound to the rest of the peptide via a linker. In some embodiments, R 1 is a reactive handle optionally bound to the rest of the peptide via a linker. In some embodiments, R1 is AEEP or MeCO. In some embodiments, R1 is AEEP. In some embodiments, R 1 is AEEP linked to E at X 13 . In some embodiments, R 1 is MeCO.
  • R 3 is K or R, or absent, wherein the K is conjugated to a reactive handle, optionally via a linker, and wherein each of K and R are L-amino acids.
  • R 3 is dK or dR, or absent, wherein the dK is conjugated to a reactive handle, optionally via a linker.
  • R3 is K conjugated to a reactive handle, optionally via a linker.
  • R3 is R.
  • R3 is absent.
  • R 3 is dK conjugated to a reactive handle, optionally via a linker.
  • R 3 is dR.
  • X4 is 4AminoPro, A, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra, each of which is an L amino acid.
  • X 4 is 4Amino-dPro, dAbu, d-aG, aMe-dC, dC, dDap, dPen, dPen(oXyl), dPen(mXyl), dPen(pXyl), or dPra.
  • X 4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra. In some embodiments, X 4 is 4AminoPro, A, Abu, Dap, Pen, or Pra. In some embodiments, X4 is 4AminoPro, Abu, Dap, Pen, or Pra. In some embodiments, X 4 is 4AminoPro, aG, Dap, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra.
  • X4 is Abu, aMeC, C, Pen, Pen(oXyl), Pen(mXyl), or Pen(pXyl). In some embodiments, X4 is Abu, aMeC, C, or Pen. In some embodiments, X4 is Abu, C, or Pen. In some embodiments, X 4 is Abu or Pen. In some embodiments, X4 is 4AminoPro. In some embodiments, X4 is 4RAminoPro. In some embodiments, X4 is 4SAminoPro. In some embodiments, X4 is A. In some embodiments, X 4 is Abu. In some embodiments, X 4 is aG. In some embodiments, X 4 is aMeC.
  • X 4 is C. In some embodiments, X 4 is Dap. In some embodiments, X 4 is Pen. In some embodiments, X4 is Pen(oXyl). In some embodiments, X4 is Pen(mXyl). In some embodiments, X 4 is Pen(pXyl). In some embodiments, X 4 is Pra. In some embodiments, X 4 is 4Amino-dPro. In some embodiments, X 4 is 4RAmino-dPro. In some embodiments, X4 is 4SAmino-dPro. In some embodiments, X4 is dA. In some embodiments, X 4 is dAbu. In some embodiments, X 4 is d-aG.
  • X 4 is aMe- dC. In some embodiments, X 4 is dC. In some embodiments, X 4 is dDap. In some embodiments, X4 is dPen. In some embodiments, X4 is dPen(oXyl). In some embodiments, X4 is dPen(mXyl). In some embodiments, X4 is dPen(pXyl). In some embodiments, X4 is dPra. In some embodiments, X 5 is N or Q, each of which is an L-amino acid. In some embodiments, X 5 is dN or dQ. In some embodiments, X 5 is N.
  • X 5 is Q. In some embodiments, X5 is dN. In some embodiments, X5 is dQ. In some embodiments, X 6 is 7MeW or T, each of which is an L-amino acid. In some embodiments, X 6 is d7MeW or dT. In some embodiments, X 6 is 7MeW. In some embodiments, X6 is T. In some embodiments, X6 is d7MeW. In some embodiments, X6 is dT. In some embodiments, X 7 is 7MeW, T, or W, each of which is an L-amino acid.
  • X 7 is d7MeW, dT, or dW. In some embodiments, X 7 is 7MeW or W. In some embodiments, X7 is 7MeW. In some embodiments, X7 is T. In some embodiments, X7 is W. In some embodiments, X7 is d7MeW. In some embodiments, X7 is dT. In some embodiments, X7 is dW. In some embodiments, X 8 is K(Ac) or Q, each of which is an L-amino acid. In some embodiments, X8 is dK(Ac) or dQ. In some embodiments, X8 is K(Ac).
  • X 8 is Q. In some embodiments, X 8 is dK(Ac). In some embodiments, X 8 is dQ. In some embodiments, X 9 is A, aMeC, aG, C, D, E, hE, Pen, or Dap(N3), each of which is an L-amino acid. In some embodiments, X9 is dA, aMe-dC, d-aG, dC, dD, dE, d-hE, dPen, or dDap(N3). In some embodiments, X 9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3).
  • X9 is A, C, D, E, hE, Pen, or Dap(N3). In some embodiments, X9 is C, D, E, hE, Pen, or Dap(N3). In some embodiments, X 9 is aG, D, E, hE, or Dap(N3). In some embodiments, X 9 is aMeC, C, or Pen. In some embodiments, X9 is aMeC or Pen. In some embodiments, X9 is aMeC. In some embodiments, X9 is aG. In some embodiments, X 9 is C. In some embodiments, X 9 is D. In some embodiments, X 9 is E.
  • X 9 is hE. In some embodiments, X 9 is Pen. In some embodiments, X 9 is Dap(N3). In some embodiments, X9 is dA. In some embodiments, X9 is aMe-dC. In some embodiments, X 9 is d-aG. In some embodiments, X 9 is dC. In some embodiments, X 9 is dD. In some embodiments, X 9 is dE. In some embodiments, X 9 is d-hE. In some embodiments, X 9 is dPen. In some embodiments, X9 is dDap(N3).
  • X 10 is 2Nal or AEF, each of which is an L-amino acid. In some embodiments, X 10 is d2Nal or dAEF. In some embodiments, X 10 is 2Nal. In some embodiments, X10 is AEF. In some embodiments, X10 is d2Nal. In some embodiments, X10 is dAEF. In some embodiments, X11 is AEF or 2Nal, each of which is an L-amino acid. In some embodiments, X 11 is dAEF or d2Nal. In some embodiments, X 11 is AEF. In some embodiments, X 11 is 2Nal. In some embodiments, X 11 is dAEF.
  • X 11 is d2Nal.
  • X12 is aMeK, K, N, or THP, wherein the K is conjugated to a reactive handle, optionally via a linker, and wherein the aMeK, K, and N are L-amino acids.
  • X 12 is d-aMeK, dK, dN, or THP, wherein the dK is conjugated to a reactive handle, optionally via a linker.
  • X12 is aMeK, K, or THP, wherein the K is conjugated to a reactive handle, optionally via a linker.
  • X 12 is aMeK.
  • X 12 is K conjugated to a reactive handle, optionally via a linker. In some embodiments, X12 is N. In some embodiments, X12 is THP. In some embodiments, X12 is d- aMeK. In some embodiments, X12 is dK conjugated to a reactive handle, optionally via a linker. In some embodiments, X 12 is dN.
  • X 13 is E, K, or K(Ac), wherein the K is conjugated to an albumin- binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker, and wherein the E, K, and K(Ac) are L-amino acids.
  • X 13 is dE, dK, or dK(Ac), wherein the dK is conjugated to an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker.
  • X 13 is E.
  • X 13 is K conjugated to an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker. In some embodiments, X13 is K conjugated to an albumin-binding moiety, optionally via a linker. In some embodiments, X 13 is K conjugated to biotin, optionally via a linker. In some embodiments, X13 is K conjugated to an imaging agent, optionally via a linker. In some embodiments, X13 is K conjugated to a second peptide, optionally via a linker. In some embodiments, X 13 is K conjugated to a reactive handle, optionally via a linker.
  • X13 is K(Ac). In some embodiments, X13 is dE. In some embodiments, X13 is dK conjugated to an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker. In some embodiments, X 13 is dK conjugated to an albumin-binding moiety, optionally via a linker. In some embodiments, X13 is dK conjugated to biotin, optionally via a linker. In some embodiments, X 13 is dK conjugated to an imaging agent, optionally via a linker.
  • X 13 is dK conjugated to a second peptide, optionally via a linker. In some embodiments, X13 is dK conjugated to a reactive handle, optionally via a linker. In some embodiments, X 13 is dK(Ac). In some embodiments, X 14 is L, 3Pya, or N, each of which is an L-amino acid. In some embodiments, X14 is dL, d3Pya, or dN. In some embodiments, X14 is dL, 3Pya, or N. In some embodiments, X14 is L. In some embodiments, X14 is 3Pya. In some embodiments, X14 is N.
  • X 14 is dL. In some embodiments, X 14 is d3Pya. In some embodiments, X 14 is dN. In some embodiments, X15 is aMeK, 3Pya, L, or THP, wherein the aMeK, 3Pya, and L are L-amino acids. In some embodiments, X 15 is d-aMeK, d3Pya, dL, or THP. In some embodiments, X 15 is aMeK, 3Pya, dL, or THP. In some embodiments, X 15 is 3Pya or dL. In some embodiments, X15 is aMeK.
  • X15 is 3Pya. In some embodiments, X 15 is L. In some embodiments, X 15 is THP. In some embodiments, X 15 is d-aMeK. In some embodiments, X 15 is d3Pya. In some embodiments, X 15 is dL. In some embodiments, X16 is K, Sar, or absent, wherein the K is conjugated to a second peptide, optionally via a linker, wherein the K is an L-amino acid. In some embodiments, X16 is dK, Sar, or absent, wherein the dK is conjugated to a second peptide, optionally via a linker.
  • X 16 is K conjugated to a second peptide, optionally via a linker. In some embodiments, X16 is dK conjugated to a second peptide, optionally via a linker. In some embodiments, X 16 is Sar. In some embodiments, X 16 is absent. In some embodiments, X 13 is E or X 15 is L. In some embodiments, X 13 is E or X 15 is dL. In some embodiments, the peptide comprises at least one moiety selected from the group consisting of an albumin-binding moiety, biotin, an imaging agent, a second peptide, and a reactive handle.
  • the peptide comprises at least one moiety selected from the group consisting of an albumin-binding moiety, biotin, an imaging agent, a second peptide, and a reactive handle at R1 or at X13.
  • the albumin-binding moiety, biotin, imaging agent, second peptide, or reactive handle is bound to the rest of the peptide via a linker. Identification, selection, and/or synthesis of a suitable linker is within the purview of one of ordinary skill in the art.
  • the linker may be an aliphatic chain.
  • the linker may be a polyethylene glycol chain (i.e., a chain containing two or more repeating units of the following structure: -CH 2 CH 2 O-).
  • the linker comprises an adduct of a click chemistry reaction, such as a triazole resulting from an alkyne-azide cycloaddition reaction.
  • the peptide comprises an albumin-binding moiety.
  • albumin-binding moiety refers to a moiety, usually a small molecule or a fragment of a small molecule, that reversibly binds to albumin in the blood and thereby increases serum circulation time of the agent to which it is attached in a subject.
  • the albumin-binding moiety is diflunisal, indomethacin, 4-(p-iodophenyl)butyric acid, or an Evans blue dye fragment. In some embodiments, the albumin-binding moiety is diflunisal or 4-(p- iodophenyl)butyric acid. In some embodiments, the albumin-binding moiety is diflunisal. In some embodiments, the albumin-binding moiety is indomethacin. In some embodiments, the albumin-binding moiety is 4-(p-iodophenyl)butyric acid. In some embodiments, the albumin- binding moiety is an Evans blue dye fragment.
  • the peptide comprises biotin. In some embodiments, the peptide comprises an imaging agent. In some embodiments, the imaging agent is a fluorescent agent. In some embodiments, the imaging agent is a radioisotope. In some embodiments, the imaging agent is a dye. In some embodiments, the imaging agent is a radioisotopically labeled polyethylene glycol chain, Cy5, or fluorescein (FITC). In some embodiments, the imaging agent is a radioisotopically labeled polyethylene glycol chain. In some embodiments, the imaging agent is Cy5. In some embodiments, the imaging agent is fluorescein (FITC). In some embodiments, the peptide is conjugated to a second peptide.
  • the imaging agent is a fluorescent agent. In some embodiments, the imaging agent is a radioisotope. In some embodiments, the imaging agent is a dye. In some embodiments, the imaging agent is a radioisotopically labeled polyethylene glycol chain, Cy5, or fluorescein (FITC). In
  • the conjugate of the peptide and the second peptide is a homodimer (i.e., the sequence of the peptide and the sequence of the second peptide are identical). In some embodiments, the conjugate of the peptide and the second peptide is a heterodimer (i.e., the sequence of the peptide and the sequence of the second peptide are not identical). In some embodiments, the second peptide is an interleukin-23 receptor inhibitor. In some embodiments, the second peptide is not an interleukin-23 receptor inhibitor. In some embodiments, the peptide comprises a reactive handle.
  • the term “reactive handle” refers to a reactive chemical moiety or functional group that may be reacted with a compatible reactive group on a second molecule to form an adduct.
  • the reactive handle is a reactive partner in a click chemistry reaction (e.g., a bioorthogonal click chemistry reaction), such as an alkyne-azide cycloaddition.
  • the reactive handle is an alkyne.
  • the reactive handle is pentynoic acid.
  • the reactive handle is an azide.
  • the reactive handle is an ⁇ -halo carbonyl.
  • the ⁇ -halo carbonyl is an ⁇ -iodo carbonyl, an ⁇ -bromo carbonyl, or an ⁇ -chloro carbonyl.
  • the peptide has a linkage between AEEP at R 1 and E at X 13 , between 4AminoPro at X 4 and D at X 9 , between 4AminoPro at X 4 and E at X 9 , between 4AminoPro at X4 and hE at X9, between aG at X4 and aG at X9, between Dap at R4 and D at R9, between Pen(mXyl) at R 4 and Pen at R 9 , between Pen(mXyl) at R 4 and Pen at R 9 , between Pen(pXyl) at R 4 and Pen at R 9 , or between Pra at R 4 and Dap(N3) at X 9 .
  • the peptide has a linkage between AEEP at R1 and E at X13, between 4AminoPro at X4 and E at X9, between 4AminoPro at X4 and hE at X9, between Dap at R 4 and D at R 9 , or between Pra at R 4 and Dap(N3) at X 9 .
  • the peptide has an amide linkage between AEEP R 1 and E at X 13 .
  • the peptide has an amide linkage between 4AminoPro at X4 and D at X 9 .
  • the peptide has an amide linkage between 4AminoPro at X 4 and E at X9.
  • the peptide has an amide linkage between 4AminoPro at X 4 and hE at X 9 . In some embodiments, the peptide has an aliphatic linkage between aG at X4 and aG at X9. In some embodiments, the peptide has an amide linkage between Dap at R 4 and D at R 9 .
  • the peptide has a thioether linkage between Pen(mXyl) at R 4 and Pen at R9 In some embodiments, the peptide has a thioether linkage between Pen(mXyl) at R 4 and Pen at R 9 In some embodiments, the peptide has a thioether linkage between Pen(pXyl) at R4 and Pen at R 9 In some embodiments, the peptide has a triazolyl linkage between Pra at R 4 and Dap(N3) at X9. In some embodiments, the peptide comprises a linkage between R 1 and X 13 having a structure selected from the following: AEEP – E.
  • the peptide is cyclized via a linkage between the residues at X 4 and X9 having a structure selected from the following: In some embodiments, the peptide is cyclized via a linkage between the residues at X 4 and X9 having a structure selected from the following:
  • the present disclosure further provides a peptide having an amino acid sequence according to any one of SEQ ID NOS: 90-136, as shown in Table 3, or a pharmaceutically acceptable salt thereof. Table 3.
  • the present disclosure provides a peptide of Formula (III), comprising the amino acid sequence: R 1 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (III), or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, MeCO, or PyE; X 6 is 3OHPro, Aib, T, or absent; X 7 is 7MeW or absent; X8 is Aib, K(Ac), K(NMeAc), R5Me, S5Me, or absent; X9 is Aib, aMePra, hC(pXyl), K, Pen, R5H, S5H, R5Me, S5Me, or absent; X 10 is 4OMeF, AEF, F, hK, R5
  • the present disclosure provides a peptide of Formula (III), comprising the amino acid sequence: R 1 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (III), or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, MeCO, or PyE; X 6 is 3OHPro, Aib, T, or absent; X7 is 7MeW or absent; X8 is Aib, K(Ac), K(NMeAc), R5Me, S5Me, or absent; X 9 is Aib, aMePra, hC(pXyl), K, Pen, R5H, S5H, R5Me, S5Me, or absent; X 10 is 4OMeF, AEF, F, hK, R
  • a peptide of Formula (III) comprising the amino acid sequence: R 1 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (III), or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, MeCO, or PyE; X 6 is 3OHPro, Aib, T, or absent; X7 is 7MeW or absent; X8 is Aib, K(Ac), K(NMeAc), R5Me, S5Me, or absent; X 9 is Aib, aMePra, hC(pXyl), K, Pen, R5H, S5H, R5Me, S5Me, or absent; X10 is 4OMeF, AEF, F, hK, R
  • R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO. In some embodiments, R 1 is 5Ava, 6Ahx, 7Ahp, or 8Aoc. In some embodiments, R 1 is 5Ava. In some embodiments, R 1 is 6Ahx. In some embodiments, R 1 is 7Ahp. In some embodiments, R 1 is 8Aoc. In some embodiments, R1 is bAla. In some embodiments, R1 is MeCO. In some embodiments, R 1 is PyE. In some embodiments, X 6 is 3OHPro, Aib, T, or absent, wherein the 3OHPro and the T are L-amino acids.
  • X6 is d-3OHPro, Aib, dT, or absent. In some embodiments, X 6 is 3OHPro. In some embodiments, X 6 is d-3OHPro. In some embodiments, X6 is Aib. In some embodiments, X6 is T. In some embodiments, X6 is dT. In some embodiments, X6 is absent. In some embodiments, X 7 is 7MeW. In some embodiments, X 7 is 7MeW, wherein the 7MeW is an L-amino acid. In some embodiments, X7 is d7MeW. In some embodiments, X7 is absent.
  • X 8 is Aib, K(Ac), K(NMeAc), R5Me, S5Me, or absent, wherein the K(Ac) and K(NMeAc) are L-amino acids.
  • X 8 is Aib, dK(Ac) dK(NMeAc), R5Me, S5Me, or absent.
  • X8 is Aib, K(Ac), or absent.
  • X 8 is R5Me or S5Me.
  • X 8 is Aib.
  • X 8 is K(Ac).
  • X 8 is dK(Ac).
  • X 8 is K(NMeAc). In some embodiments, X8 is dK(NMeAc). In some embodiments, X8 is R5Me. In some embodiments, X 8 is S5Me. In some embodiments, X 8 is absent. In some embodiments, X 9 is Aib, aMePra, hC(pXyl), K, Pen, R5H, S5H, R5Me, S5Me, or absent, wherein the aMePra, hC(pXyl), K, and Pen are L-amino acids.
  • X9 is Aib, d-aMePra, d-hC(pXyl), dK, dPen, R5H, S5H, R5Me, S5Me, or absent.
  • X 9 is aMePra, hC(pXyl), K, RS5, S5H, R5Me, S5Me, or absent.
  • X 9 is K, R5H, S5H, S5Me, S5Me, or absent.
  • X 9 is Aib.
  • X9 is aMePra.
  • X9 is d-aMePra. In some embodiments, X 9 is hC(pXyl). In some embodiments, X 9 is d-hC(pXyl). In some embodiments, X 9 is K. In some embodiments, X 9 is dK. In some embodiments, X 9 is Pen. In some embodiments, X9 is dPen. In some embodiments, X9 is R5H. In some embodiments, X9 is S5H. In some embodiments, X 9 is R5Me. In some embodiments, X 9 is S5Me. In some embodiments, X 9 is absent.
  • X10 is 4OMeF, AEF, F, hK, R5H, S5H, or absent, wherein the 4OMeF, AEF, F, and hK are L-amino acids.
  • X10 is d4OMeF, dAEF, dF, d-hK, R5H, S5H, or absent.
  • X 10 is 4OMeF, AEF, F, hK, R5Me, S5H, or absent.
  • X 10 is AEF, hK, R5H, S5H, or absent.
  • X 10 is 4OMeF.
  • X10 is d4OMeF. In some embodiments, X10 is AEF. In some embodiments, X 10 is dAEF. In some embodiments, X 10 is F. In some embodiments, X 10 is dF. In some embodiments, X 10 is hK. In some embodiments, X 10 is d-hK. In some embodiments, X 10 is R5Me. In some embodiments, X10 is S5Me. In some embodiments, X10 is absent. In some embodiments, X 11 is 2Nal or 6OH2Nal, each of which is an L-amino acid. In some embodiments, X 11 is d2Nal or d6OH2Nal.
  • X 11 is 2Nal. In some embodiments, X 11 is d2Nal. In some embodiments, X 11 is 6OH2Nal. In some embodiments, X 11 is d6OH2Nal. In some embodiments, X12 is aMeK, R5Me, S5Me, or THP, wherein the aMeK is an L- amino acid. In some embodiments, X 12 is d-aMeK, R5Me, S5Me, or THP. In some embodiments, X12 is aMeK or THP. In some embodiments, X12 is R5Me or S5Me. In some embodiments, X12 is aMeK.
  • X12 is d-aMeK. In some embodiments, X12 is R5Me. In some embodiments, X 12 is S5Me. In some embodiments, X 12 is THP. In some embodiments, X 13 is aMeK(N3), E, hC, hE, K(Ac), Q, R5H, S5H, R5Me, or S5Me, wherein the aMeK(N3), E, hC, hE, K(Ac), and Q are L-amino acids.
  • X 13 is d-aMeK(N3), dE, d-hC, d-hE, dK(Ac), dQ, R5H, S5H, R5Me, or S5Me.
  • X 13 is aMeK(N3), E, hC, hE, Q, R5H, S5H, R5Me, or S5Me.
  • X13 is E, hE, Q, R5H, S5H, R5Me, or S5Me.
  • X13 is E, hE, or Q.
  • X 13 is aMeK(N3).
  • X 13 is d-aMeK(N3). In some embodiments, X 13 is E. In some embodiments, X 13 is dE. In some embodiments, X 13 is hC. In some embodiments, X13 is d-hC. In some embodiments, X13 is hE. In some embodiments, X13 is d-hE. In some embodiments, X13 is K(Ac). In some embodiments, X13 is dK(Ac). In some embodiments, X 13 is Q. In some embodiments, X 13 is dQ. In some embodiments, X 13 is R5H. In some embodiments, X 13 is S5H.
  • X 13 is R5Me. In some embodiments, X 13 is S5Me. In some embodiments, X 14 is D, hE, N, R5H, or S5H, wherein the D, hE, and N are L- amino acids. In some embodiments, X 14 is dD, d-hE, dN, R5H, or S5H. In some embodiments, X14 is D or N. In some embodiments, X14 is R5H or S5H. In some embodiments, X14 is D. In some embodiments, X 14 is dD. In some embodiments, X 14 is hE. In some embodiments, X 14 is d- hE.
  • X 14 is N. In some embodiments, X 14 is dN. In some embodiments, X14 is R5H. In some embodiments, X14 is S5H. In some embodiments, X15 is 3Pya or N, each of which is an L-amino acid. In some embodiments, X 15 is d3Pya or dN. In some embodiments, X 15 is 3Pya. In some embodiments, X 15 is N. In some embodiments, X 15 is d3Pya. In some embodiments, X 15 is dN.
  • X16 is N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(iBu)Gly, Sar, or absent. In some embodiments, X 16 is N(3AmBenzyl)Gly, Sar, or absent. In some embodiments, X 16 is Sar or absent. In some embodiments, X 16 is N(3AmBenzyl)Gly. In some embodiments, X16 is N(Cyclohexyl)Gly. In some embodiments, X16 is N(iBu)Gly. In some embodiments, X16 is Sar. In some embodiments, X 16 is absent. In some embodiments, R 2 is CONH2. In some embodiments, R 2 is CONH(PEG3a).
  • X6 is absent, and X7, X8, X9, and X10 are not absent.
  • X 6 and X 7 are absent, and X 8 , X 9 , and X 10 are not absent.
  • X6, X7, and X8 are absent, and X9 and X10 are not absent.
  • X6, X7, X8, and X9 are absent, and X10 is not absent.
  • X 6 , X 7 , X 8 , X 9 , and X 10 are absent.
  • the peptide contains one linkage selected from the group consisting of a linkage between R1 and X13, a linkage between R1 and X14, a linkage between X8 and X 12 , a linkage between X 9 and X 13 , a linkage between X 10 and X 13 , and a linkage between X 10 and X 14.
  • the peptide contains a linkage between R1 and X13.
  • the linkage between R 1 and X 13 has a structure selected from the following:
  • the peptide contains a linkage between R1 and X14.
  • the linkage between R 1 and X 14 has a structure selected from the following: In some embodiments, the peptide contains a linkage between X8 and X12. In some embodiments, the linkage between X8 and X12 has a structure selected from the following: In some embodiments, the peptide contains a linkage between X9 and X13. In some embodiments, the linkage between X 9 and X 13 has a structure selected from the following: In some embodiments, the peptide contains a linkage between X10 and X13. In some embodiments, the linkage between X10 and X13 has the following structure : . AEF – E.
  • the peptide contains a linkage between X 10 and X 14 .
  • the linkage between X10 and X14 has a structure selected from the following:
  • the peptide comprises an amino acid sequence selected from any of the following formulas: R1-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III-A), R 1 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (III-B), R 1 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (III-C), R1-X10-X11-X12-X13-X14-X15-X16-R2 (III-D), and R1-X11-X12-X13-X14-X15-X16-R2 (III-D), and R1
  • the peptide comprises the amino acid sequence of Formula (III- A): R 1 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (III-A) or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO; X 7 is 7MeW or absent; 739659: NTT-4251PC X 8 is Aib, K(Ac) or absent; X9 is aMePra, hC(pXyl), K, RS5, S5H, R5Me, S5Me, or absent; X10 is 4OMeF, AEF, F, hK, R5Me, S5H, or absent; X 11 is 2Nal or 6OH2Nal; 5 X12 is aMeK or THP;
  • the peptide comprises the amino acid sequence of Formula (III- B): R 1 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (III-B) or a pharmaceutically acceptable salt thereof, wherein: 15 R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO; X8 is Aib, K(Ac) or absent; X 9 is K, R5H, S5H, S5Me, S5Me, or absent; X 10 is AEF, hK, R5H, S5H, or absent; X11 is 2Nal or 6OH2Nal; 20 X 12 is aMeK or THP; X 13 is E, hE, Q, R5H, S5H, R5Me, or S5Me; X14 is D, hE, N, R5H, or S
  • the peptide comprises the amino acid sequence of Formula (III- C): R 1 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (III-C), or a pharmaceutically acceptable salt thereof, wherein: 30 R 1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO; X 9 is K, R5H, S5H, R5Me, S5Me, or absent; X10 is AEF, hK, R5H, S5H, or absent; X 11 is 2Nal or 6OH2Nal; X 12 is aMeK or THP; 35 X13 is E, hE, Q, R5H, S5H, R5Me, or S5Me; 216 X 14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is
  • the peptide comprises the amino acid sequence of Formula (III- D): R 1 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (III-D) or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO; X 10 is AEF, hK, R5H, S5H, or absent; X 11 is 2Nal or 6OH2Nal; X12 is THP; X 13 is E, hE, or Q; X 14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is Sar; and R 2 is CONH2.
  • the peptide comprises the amino acid sequence of Formula (III- E): R 1 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -R 2 (III-E) or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, or 8Aoc; X 11 is 2Nal or 6OH2Nal; X 12 is THP; X13 is E, hE, or Q; X14 is D or N; X 15 is 3Pya; X 16 is Sar; and R2 is CONH2.
  • the present disclosure further provides a peptide having an amino acid sequence according to any one of SEQ ID NOS: 137-174, as shown in Table 4, or a pharmaceutically acceptable salt thereof. Table 4.
  • the present disclosure provides a method of chemically synthesizing a peptide of the present disclosure.
  • a portion of the peptide is recombinantly synthesized, instead of being chemically synthesized.
  • methods of producing a peptide further include cyclizing the peptide precursor after the constituent subunits have been attached.
  • cyclization is accomplished via any of the various methods described herein.
  • the present disclosure further describes synthesis of compounds described herein.
  • one or more of the amino acid residues or amino acid monomers are lipidated and then covalently attached to one another to form a peptide of the disclosure.
  • one or more of the amino acid residues or amino acid monomers are covalently attached to one another and lipidated at an intermediate oligomer stage before attaching additional amino acids and cyclization to form a peptide of the disclosure.
  • a cyclic peptide is synthesized and then lipidated to form a compound of the disclosure. Illustrative synthetic methods are described in the Examples.
  • Pharmaceutical Compositions The present disclosure further relates to a pharmaceutical composition comprising an IL-23R inhibitor described herein.
  • the present disclosure includes pharmaceutical compositions comprising one or more peptides of the present disclosure and a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutically acceptable carrier, diluent or excipient may be a solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like.
  • compositions may be administered orally, parenterally, intracisternally, intravaginally, intraperitoneally, intrarectally, topically (as by powders, ointments, drops, suppository, or transdermal patch), by inhalation (such as intranasal spray), ocularly (such as intraocularly) or buccally.
  • parenteral refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal and intraarticular injection and infusion. Accordingly, in certain embodiments, the compositions are formulated for delivery by any of these routes of administration.
  • a pharmaceutical composition may be formulated for and administered orally.
  • a pharmaceutical composition may be formulated for and administered parenterally.
  • the IL-23R inhibitors of the present disclosure may be prepared and/or formulated as pharmaceutically acceptable salts and/or other forms thereof or when appropriate in neutral form.
  • Pharmaceutically acceptable salts are non-toxic salts of a neutral form of a compound that possess the desired pharmacological activity of the neutral form. These salts may be derived from inorganic or organic acids or bases. For example, a compound that contains a basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid.
  • Non-limiting examples of pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.
  • the present disclosure relates to pharmaceutical compositions comprising an IL-23R inhibitor described herein or pharmaceutically acceptable salts, isomers, or a mixture thereof, in which one or more hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D.
  • the deuterium atom is a non-radioactive isotope of the hydrogen atom.
  • Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol.
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.
  • isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • Isotopically-labeled peptides of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • a peptide inhibitor of the present disclosure may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form.
  • the total daily usage of the IL-23R inhibitor and compositions of the present disclosure can be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including: a) the disorder being treated and the severity of the disorder; b) activity of the specific compound employed; c) the specific composition employed, the age, body weight, general health, sex and diet of the patient; d) the time of administration, route of administration, and rate of excretion of the specific peptide inhibitor employed; e) the duration of the treatment; f) drugs used in combination or coincidental with the specific peptide inhibitor employed, and like factors well known in the medical arts.
  • compositions may conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Techniques and compositions generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • the IL-23R inhibitors of the present disclosure may be used for detection, assessment and diagnosis of intestinal inflammation by microPET imaging, wherein the peptide inhibitor is labeled with a chelating group or a detectable label, as part of a non-invasive diagnostic procedure.
  • an IL-23R inhibitor of the present disclosure is conjugated with a bifunctional chelator.
  • an IL-23R inhibitor of the present disclosure is radiolabeled. The labeled IL-23R inhibitor is then administered to a subject orally or rectally. In certain embodiments, the IL-23R inhibitor is included in drinking water.
  • microPET imaging may be used to visualize inflammation throughout the subject’s bowels and digestive track.
  • Methods of Treatment and Uses The present disclosure relates to methods for treating a subject afflicted with a condition or indication associated with IL-23 or IL-23R activity (e.g., activation of the IL-23/IL-23R signaling pathway), wherein the method comprises administering to the subject an IL-23R inhibitor disclosed herein.
  • the present disclosure provides a method for treating a subject afflicted with a condition or indication characterized by aberrant or dysregulated IL-23 or IL-23R activity or signaling, comprising administering to the subject a peptide inhibitor of the present disclosure in an amount sufficient to inhibit (partially or fully) binding of IL-23 to an IL- 23R in the subject.
  • the inhibition of IL-23 binding to IL-23R may occur in particular organs or tissues of the subject, e.g., the stomach, small intestine, large intestine/colon, intestinal mucosa, lamina intestinal, Peyer’s Patches, mesenteric lymph nodes, or lymphatic ducts.
  • the present disclosure relates to methods comprising providing a peptide inhibitor described herein to a subject in need thereof.
  • the subject in need thereof may be a subject that has been diagnosed with or has been determined to be at risk of developing a disease or disorder associated with IL-23/IL-23R.
  • the subject may be a mammal.
  • the subject may be, in particular, a human.
  • the disease or disorder to be treated by treatment with an IL-23R inhibitor of the present disclosure may be an inflammatory disease or disorder, an autoimmune inflammation diseases or disorder, and/or related disorders, including multiple sclerosis, asthma, rheumatoid arthritis, inflammation of the gut, inflammatory bowel diseases (IBDs), juvenile IBD, adolescent IBD, Crohn’s disease, ulcerative colitis, sarcoidosis, Systemic Lupus Erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, or psoriasis.
  • IBDs inflammatory bowel diseases
  • juvenile IBD juvenile IBD
  • adolescent IBD Crohn’s disease
  • ulcerative colitis sarcoidosis
  • Systemic Lupus Erythematosus ankylosing spondylitis (axial spondyloarthritis)
  • psoriatic arthritis or psoriasis.
  • the disease or disorder may be psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, Palmo-Plantar Pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, acne ectopica, ulcerative colitis, Crohn’s disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis/esophagitis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott
  • the present disclosure provides a method or use of an IL-23R inhibitor for treating an inflammatory disease or disorder in a subject in need thereof that includes administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present disclosure, a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising an IL-23 inhibitor of the present disclosure.
  • the present disclosure provides a method or use of an IL-23R inhibitor for treating an autoimmune disease or disorder in a subject in need thereof that includes administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present disclosure, a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising an IL-23 inhibitor of the present disclosure.
  • the present disclosure provides a method or use of an IL-23R inhibitor for treating an autoimmune inflammation disease or disorder in a subject in need thereof that includes administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present disclosure, a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising an IL-23 inhibitor of the present disclosure.
  • Suitable inflammatory diseases, autoimmune inflammation diseases, and/or related disorders for treatment with a compound or pharmaceutically acceptable salt thereof, or a composition of the present disclosure may include, but are not limited to inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA) and the like.
  • the inflammatory disease to be treated may be inflammatory bowel disease (IBD), Crohn’s disease, or ulcerative colitis.
  • the inflammatory disease to be treated may be selected from psoriasis or psoriatic arthritis.
  • the inflammatory disease to be treated may be psoriasis
  • the inflammatory disease to be treated may be psoriatic arthritis.
  • the inflammatory disease to be treated may be IBD.
  • the inflammatory disease to be treated may be Crohn’s disease.
  • the inflammatory disease to be treated may be ulcerative colitis.
  • IL-23 Production of IL-23 is enriched in the intestine, where it is believed to play a key role in regulating the balance between tolerance and immunity through T-cell-dependent and T-cell- independent pathways of intestinal inflammation through effects on T-helper 1 (Th1) and Th17- associated cytokines, as well as restraining regulatory T-cell responses in the gut, favoring inflammation.
  • Th1 T-helper 1
  • Th17- associated cytokines T-helper 1
  • IL-23R polymorphisms in the IL-23 receptor
  • IBDs inflammatory bowel diseases
  • Peptides and methods for specific targeting of the IL-23R from the luminal side of the gut may provide therapeutic benefit to IBD patients suffering from local inflammation of the intestinal tissue.
  • the present disclosure also provides a method of treating or preventing inflammatory bowel disease (IBD), Crohn’s disease (CD), or ulcerative colitis (UC), in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a peptide of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein comprising an IL-23 inhibitor.
  • the method is for treating or preventing inflammatory bowel disease (IBD).
  • the method is for treating or preventing Crohn’s disease (CD).
  • the method is for treating or preventing ulcerative colitis (UC).
  • IL-23 is one of several interleukins implicated as a key player in the pathogenesis of psoriasis, purportedly by maintaining chronic autoimmune inflammation via the induction of interleukin- 17, regulation of T memory cells, and activation of macrophages.
  • Expression of IL-23 and IL- 23R has been shown to be increased in tissues of patients with psoriasis, and antibodies that neutralize IL-23 showed IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.
  • Orally bioavailable peptide inhibitors of IL-23 may provide both a non-steroidal treatment option for patients with mild to moderate psoriasis and treatment for moderate to severe psoriasis that does not require delivery by infusion. Accordingly, the present disclosure also provides a method of treating or preventing psoriasis (PsO) or psoriatic arthritis (PsA) in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a peptide of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein comprising an IL-23 inhibitor. In some embodiments, the method is for treating or preventing psoriasis (PsO).
  • PsO psoriasis
  • PsA psoriatic arthritis
  • the method is for treating or preventing psoriasis (PsO).
  • the method is for treating or preventing psoriatic arthritis (PsA).
  • PsA psoriatic arthritis
  • the present disclosure further relates to a method of selectively inhibiting IL-23 or IL- 23R signaling (or the binding of IL-23 to IL-23R) in a subject (e.g., in a subject in need thereof), comprising administering to the subject a peptide inhibitor of the IL-23R described herein.
  • the present disclosure includes and provides a method of selectively inhibiting IL-23 or IL-23R signaling (or the binding of IL-23 to IL-23R) in the GI tract of a subject (e.g., a subject in need thereof), comprising providing to the subject a peptide inhibitor of the IL-23R of the present disclosure by oral administration.
  • the exposure of GI tissues (e.g., small intestine or colon) to the administered peptide inhibitor may be at least 10-fold, at least 20- fold, at least 50-fold, or at least 100-fold greater than the exposure (level) in the blood.
  • the present disclosure includes a method of selectively inhibiting IL23 or IL23R signaling (or the binding of IL23 to IL23R) in the GI tract of a subject (e.g., a subject in need thereof), comprising providing to the subject a peptide inhibitor, wherein the peptide inhibitor does not block the interaction between IL-6 and IL-6R or antagonize the IL-12 signaling pathway.
  • the present disclosure provides a method of inhibiting GI inflammation and/or neutrophil infiltration to the GI, comprising providing to a subject in need thereof a peptide inhibitor of the present disclosure.
  • methods of the present disclosure comprise providing a peptide inhibitor of the present disclosure (i.e., a first therapeutic agent) to a subject (e.g., a subject in need thereof) in combination with a second therapeutic agent.
  • the second therapeutic agent is provided to the subject before and/or simultaneously with and/or after the peptide inhibitor is administered to the subject.
  • the second therapeutic agent is an anti-inflammatory agent.
  • the second therapeutic agent is a non- steroidal anti-inflammatory drug, steroid, or immune modulating agent.
  • the method comprises administering to the subject a third therapeutic agent.
  • the second therapeutic agent is an antibody that binds IL-23 or IL-23R.
  • the present disclosure also relates to methods of inhibiting IL-23 binding to an IL-23R on a cell, comprising contacting the IL-23R with a peptide inhibitor of the receptor disclosed herein.
  • the cell may be a mammalian cell.
  • the method may be performed in vitro or in vivo. Inhibition of binding may be determined by a variety of routine experimental methods and assays known in the art.
  • the present disclosure relates to methods of inhibiting IL-23 signaling by a cell, comprising contacting the IL-23R with a peptide inhibitor described herein.
  • the cell is a mammalian cell.
  • the method is performed in vitro or in vivo.
  • the inhibition of IL-23 signaling may be determined by measuring changes in phospho-STAT3 levels in the cell.
  • the following examples are not intended to limit the scope of the present disclosure, but rather to provide guidance to the skilled artisan to prepare and use the peptides, compositions, and methods of the present disclosure. While particular aspects of the present disclosure are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the disclosure. Some abbreviations useful in describing the disclosure are defined below in the following tables. Herein and throughout the application, the following abbreviations may be used. Table 6. N-Terminal Modification Abbreviations
  • Example 1 General Procedure for Solid-Phase Synthesis of Peptides Peptide were chemically synthesized using optimized 9-fluorenylmethoxy carbonyl (Fmoc) solid phase peptide synthesis protocols. For C-terminal amides, Rink-amide MBHA resin was used. The side chain protecting groups were as follows: Lys: iv-dde; d-Arg: Pbf; Thr, Glu: O-tButyl; Asn, Pen, Cys, aMeCys: Trityl; AEF: Boc.
  • Fmoc 9-fluorenylmethoxy carbonyl
  • HPLC Method A Description: Mobile Phase: 0.075% TFA in water (solvent A) and acetonitrile (solvent B)
  • solvent A acetonitrile
  • the peptide was synthesized using standard Fmoc chemistry. 1) DMF and MBHA Resin (0.20 mmol, 0.60 g, sub: 0.33 mmol/g) were combined in a vessel, and the resin was allowed to swell for two hours. 2) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 3) The resin was then drained and washed with DMF for 30 seconds*5 times. 4) Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds before addition of a solution of HATU and DIEA in DMF. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min.
  • Steps 2 to 5 were repeated for subsequent amino acid couplings.
  • the coupling reactions were monitored by ninhydrin or tetrachlor color test, and upon completion, the resin was washed with DMF 5 times. Once peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum. Monitoring method: 1.
  • Ninhydrin test A: 5% ninhydrin /EtOH; B: 80% phenol /EtOH; C: pyridine 2.
  • Tetrachlor color test A: 2% tetrachlor/ DMF; B: 2% aldehyde/ DMF 110 o C for 3min Peptide Cleavage: 1) To the flask containing the side chain protected peptide at room temperature was added 30 mL cleavage buffer (5.0% DTT /2.5% H2O /2.5% TIS /90%TFA), and mixture was stirred for 3 hrs. 2) The mixture was filtered and washed with 5 mL TFA. The combined filtrate was triturated with cold methyl tertbutyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged.
  • MTBE cold methyl tertbutyl ether
  • the peptide was synthesized using standard Fmoc chemistry. 1) DMF and MBHA Resin (0.30 mmol, 0.96 g, sub: 0.31 mmol/g) were combined in a vessel, and the resin was allowed to swell for two hours. 2) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 3) The resin was then drained and washed with DMF for 30 seconds*5 times. 4) Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds before addition of a solution of HATU and DIEA in DMF. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min.
  • Steps 2 to 5 were repeated for subsequent amino acid couplings.
  • the coupling reactions were monitored by ninhydrin or tetrachlor color test, and upon completion, the resin was washed with DMF 5 times. Once peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum. Monitoring method: 1.
  • Ninhydrin test A: 5% ninhydrin /EtOH; B: 80% phenol /EtOH; C: pyridine 2.
  • Tetrachlor color test A: 2% tetrachlor/ DMF; B: 2% aldehyde/ DMF 110 o C for 3min Peptide Cleavage: 1) To the flask containing the side chain protected peptide at room temperature was added 30 mL cleavage buffer (5.0% DTT /2.5% H 2 O /2.5% TIS /90%TFA), and mixture was stirred for 3 hrs. 2) The mixture was filtered and washed with 5 mL TFA. The combined filtrate was triturated with cold methyl tertbutyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged.
  • MTBE cold methyl tertbutyl ether
  • the peptide was synthesized using standard Fmoc chemistry.
  • the resin was washed with 20 mL of DMF (5x0.1 min) followed by addition of 1.5 mL of Fmoc-4-Br-L-HomoAla-OH in DMF (400 mM) and 1.5 mL of coupling reagent HOAT in DMF (400 mM) and DIC (92 uL).
  • the coupling reaction was mixed for 16hrs and then washed with 20 mL of DMF (5x0.1 min). The coupling was repeated one more time for 16 ⁇ 32hrs. After completing the coupling reaction, the resin was washed with 30 mL of DMF (3x0.1 min).
  • the peptide was synthesized using standard Fmoc chemistry. 1) DMF and MBHA Resin (0.6 mmol, 2.6 g, sub: 0.23 mmol/g) were combined in a vessel, and the resin was allowed to swell for two hours. 2) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 3) The resin was then drained and washed with DMF for 30 seconds*5 times. 4) Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds before addition of a solution of HATU and DIEA in DMF. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min.
  • Steps 2 to 5 were repeated for subsequent amino acid couplings.
  • the coupling reactions were monitored by ninhydrin or tetrachlor color test, and upon completion, the resin was washed with DMF 5 times. Once peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum. Monitoring method: 1.
  • Ninhydrin test A: 5% ninhydrin /EtOH; B: 80% phenol /EtOH; C: pyridine 2.
  • Tetrachlor color test A: 2% tetrachlor/ DMF; B: 2% aldehyde/ DMF 110 o C for 3min
  • Synthetic method for thioether cyclization Coupling of Fmoc-4-Br-L-HomoAla-OH. After de-protection, the resin was washed with 20 mL of DMF (5x0.1 min) followed by addition of 1.5 mL of Fmoc-4-Br-L-HomoAla-OH in DMF (400 mM) and 1.5 mL of coupling reagent HOAT in DMF (400 mM) and DIC (92 uL).
  • the coupling reaction was mixed for 16hrs and then washed with 20 mL of DMF (5x0.1 min). The coupling was repeated one more time for 16 ⁇ 32hrs. After completing the coupling reaction, the resin was washed with 30 mL of DMF (3x0.1 min).
  • De-Trt of aMeCys The resin was washed with 30 mL of DMF (5x0.1 min) and DCM (5x0.1 min) followed by addition of 2.5% TFA and 2.5%TIS in DCM (20 mL) (the reaction solution changed from orange to colorless).
  • the resin was then washed with DCM, 5% DIEA in DMF and DMF 3 times Thioether cyclization on resin: The resin was washed with 30 mL of DMF (5x0.1 min) followed by addition of DIEA (5 eq) in DMF (50 mL). The suspension was mixed for 1h. Cleavage test and LCMS showed the reaction had finished. After completing the coupling reaction, the resin was washed with 30 mL of DMF (3x0.1 min).
  • Peptide Cleavage 1) To the flask containing the side chain protected peptide at room temperature was added 30 mL cleavage buffer (5.0% DTT /2.5% H2O /2.5% TIS /90%TFA), and mixture was stirred for 3 hrs. 2) The mixture was filtered and washed with 5 mL TFA. The combined filtrate was triturated with cold methyl tertbutyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged.
  • MTBE cold methyl tertbutyl ether
  • the peptide was synthesized using standard Fmoc chemistry. 1) DMF and MBHA Resin (0.20 mmol, 0.60 g, sub: 0.33 mmol/g) were combined in a vessel, and the resin was allowed to swell for two hours. 2) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 3) The resin was then drained and washed with DMF for 30 seconds*5 times. 4) Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds before addition of a solution of HATU and DIEA in DMF. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min.
  • Steps 2 to 5 were repeated for subsequent amino acid couplings.
  • the coupling reactions were monitored by ninhydrin or tetrachlor color test, and upon completion, the resin was washed with DMF 5 times. Once peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum. Monitoring method: 1.
  • Ninhydrin test A: 5% ninhydrin /EtOH; B: 80% phenol /EtOH; C: pyridine 2.
  • Tetrachlor color test A: 2% tetrachlor/ DMF; B: 2% aldehyde/ DMF 110 o C for 3min Peptide Cleavage: 1) To the flask containing the side chain protected peptide at room temperature was added 30 mL cleavage buffer (5.0% DTT /2.5% H 2 O /2.5% TIS /90%TFA), and mixture was stirred for 3 hrs. 2) The mixture was filtered and washed with 5 mL TFA. The combined filtrate was triturated with cold methyl tertbutyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged.
  • MTBE cold methyl tertbutyl ether
  • the peptide was synthesized using standard Fmoc chemistry. 1) DMF and MBHA Resin (0.20 mmol, 0.60 g, sub: 0.33 mmol/g) were combined in a vessel, and the resin was allowed to swell for two hours. 2) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 3) The resin was then drained and washed with DMF for 30 seconds*5 times. 4) Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds before addition of a solution of HATU and DIEA in DMF. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min.
  • Steps 2 to 5 were repeated for subsequent amino acid couplings.
  • the coupling reactions were monitored by ninhydrin or tetrachlor color test, and upon completion, the resin was washed with DMF 5 times. Once peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum. Monitoring method: 1.
  • Ninhydrin test A: 5% ninhydrin /EtOH; B: 80% phenol /EtOH; C: pyridine 2.
  • Tetrachlor color test A: 2% tetrachlor/ DMF; B: 2% aldehyde/ DMF 110 o C for 3min
  • Synthetic method for removal of ivDde protecting group Deprotection of ivDde on Lys: The resin was washed with 50 mL of DMF (5x0.1 min) followed by addition of 3% hydrazine hydrate in DMF (50 mL). The reaction was allowed to proceed for 20 (ninhydrin color reaction) before the resin was washed with DMF 5 times.
  • Peptide Cleavage 1) To the flask containing the side chain protected peptide at room temperature was added 30 mL cleavage buffer (5.0% DTT /2.5% H2O /2.5% TIS /90%TFA), and mixture was stirred for 3 hrs. 2) The mixture was filtered and washed with 5 mL TFA. The combined filtrate was triturated with cold methyl tertbutyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged.
  • MTBE cold methyl tertbutyl ether
  • Example 8 IL23R Reporter Assay Compounds were serially diluted in 100% (v/v) DMSO) and plated using an Echo acoustic dispenser (Labcyte) into 1536-well non-treated black assay plates (Corning # 9146). 3 ⁇ L of HEK293 cells containing IL-23R, IL-12R ⁇ 1 and a firefly luciferase reporter gene driven by a STAT-inducible promoter (Promega) were added to the plates (4000 cells/well), followed by 3 ⁇ L of 10 ng/mL IL-23 (equivalent to EC90 concentration).
  • PBMC pSTAT3 Assay Cryopreserved peripheral blood mononuclear cells (PBMCs) from healthy donors were thawed and washed twice in ImmunoCult-XF T cell expansion medium (XF-TCEM) supplemented with CTL anti-aggregate wash.
  • PBMCs peripheral blood mononuclear cells
  • the cells were counted, resuspended at 2-6x10 5 cells per mL XF-TCEM supplemented with penicillin/streptomycin and 100 ng/mL IL-1 ⁇ (BioLegend, 579404), and cultured in tissue culture flasks coated with anti-CD3 (eBioscience, 16-0037-85 or BD Pharmingen, 555329) at 37oC in 5% CO2.
  • PBMCs were collected, washed twice in RPMI-1640 supplemented with 0.1% BSA (RPMI-BSA), and incubated in RPMI-BSA in upright tissue culture flasks for ⁇ 4 hours at 37oC in 5% CO2.
  • a total of 6x104 cells in 30 ⁇ L RPMI-BSA was transferred into each well of a 384-well plate pre-spotted with peptide or DMSO.
  • the cells were incubated for 30 minutes prior to the addition of IL-23 at a final concentration of 5 ng/mL.
  • the cells were stimulated with cytokine for 30 minutes at 37oC in 5% CO2, transferred onto ice for 10 minutes, and lysed.
  • Cell lysates were stored at -80°C until phosphorylated STAT3 was measured using the phospho-STAT panel kit (Meso Scale Discovery, K15202D). Results are provided below.

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Abstract

The present disclosure relates to peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, methods and/or uses for treatment of autoimmune inflammation and related diseases and disorders.

Description

PEPTIDE INHIBITORS OF INTERLEUKIN-23 RECEPTOR CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.63/480,041 filed January 16, 2023, which is herein incorporated by reference in its entirety. INCORPORATION OF SEQUENCE LISTING The sequence listing in ST.26 XML format entitled 739659_NTT-4251PC_SL, created on January 12, 2024, comprising 585,087 bytes, prepared according to 37 CFR 1.822 to 1.824, submitted concurrently with the filing of this application, is incorporated herein by reference in its entirety. BACKGROUND The interleukin-23 (IL-23) cytokine is a heterodimer composed of a unique p19 subunit and the p40 subunit shared with IL-12, which is a cytokine involved in the development of interferon- ^ (IFN- ^)-producing T helper 1 (TH1) cells. Although IL-23 and IL-12 both contain the p40 subunit, they have different phenotypic properties. For example, animals deficient in IL- 12 are susceptible to inflammatory autoimmune diseases, whereas IL-23 deficient animals are resistant to these diseases, presumably due to a reduced number of CD4+ T cells producing IL-6, IL-17, and TNF in the CNS of IL-23-deficient animals. IL-23 binds to IL-23R, which is a heterodimeric receptor composed of IL-12Rβ1 and IL-23R subunits. Binding of IL-23 to IL-23R activates the Jak-Stat signaling molecules Jak2, Tyk2, Stat1, Stat 3, Stat 4, and Stat 5, although Stat4 activation is substantially weaker and different DNA-binding Stat complexes form in response to IL-23 as compared with IL-12. IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with Stat3. In contrast to IL-12, which acts mainly on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells. IL-23 has been implicated as playing a crucial role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn’s disease. Studies in acute and chronic mouse models of IBDs revealed a primary role of interleukin-23 receptor (IL-23R) and downstream effector cytokines in disease pathogenesis. IL-23R is expressed on various adaptive and innate immune cells including Th17 cells, γδ T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are found abundantly in the intestine. At the intestine mucosal surface, the gene expression and protein levels of IL-23R are found to be elevated in IBD patients. It is believed that IL-23 mediates this effect by promoting the development of a pathogenic CD4+ T cell population that produces IL-6, IL-17, and tumor necrosis factor (TNF). Accordingly, there remains a need for compositions that bind IL-23R to inhibit IL-23 binding and signaling in a patient. BRIEF SUMMARY Provided herein are peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, and methods and/or uses of the IL-23R inhibitors for the treatment of inflammatory diseases, autoimmune diseases, and/or related disorders. In particular, the present disclosure provides a peptide of Formula (I), comprising the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I), or a pharmaceutically acceptable salt thereof, wherein X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, and X16 are defined herein. In another aspect, the present disclosure provides a peptide of Formula (II), comprising the amino acid sequence: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (II), or a pharmaceutically acceptable salt thereof, wherein R1, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, R2 are defined herein. In another aspect, the present disclosure provides a peptide of Formula (III), comprising the amino acid sequence: R1-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III), or a pharmaceutically acceptable salt thereof, wherein R1, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, R2 are defined herein. The present disclosure further provides a pharmaceutical composition comprising a peptide described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present disclosure still further provides a method for treating a disease or disorder associated with Interleukin 23 (IL-23)/Interleukin 23 Receptor (IL-23R), comprising administering to a subject in need thereof a therapeutically effective amount of a peptide or a pharmaceutical composition described herein. In some embodiments, the disease or disorder is selected from ulcerative colitis (UC), Crohn’s disease (CD), psoriasis (PsO), and psoriatic arthritis (PsA). DETAILED DESCRIPTION Provided herein are peptide inhibitors of IL-23R, and pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, and methods and/or uses for the treatment of inflammatory diseases, autoimmune diseases, and/or related disorders. Definitions Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. As used in the specification and in the claims, the “comprise(s),” “comprising,” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named features, groups, ingredients, or steps and does not exclude the presence of additional features, groups, ingredients, or steps. For example, the language “a peptide of Formula (I), comprising the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X10-X11- X12-X13-X14- X15-X16 (I),” means that in addition to amino acids X3 through X16, the peptide may include but is not limited to additional amino acids attached to the N-terminus , additional amino acids attached to the C-terminus, N-terminal or C-terminal capping groups, chemical or biological moieties (including but not limited to, for example, lipophilic substituents, antibodies, imaging agents, etc.) conjugated to the peptide at any location, and the like. The term “comprise(s),” “comprising,” “include(s),” “having,” “has,” “can,” or “contain(s),” can include embodiments encompassed by the term "consisting essentially of" or "consisting of." The terms “peptide,” “polypeptide,” and “protein” are used interchangeably herein and typically refer to a molecule comprising a chain of two or more amino acids (e.g., L-amino acids, D-amino acids, modified amino acids, amino acid analogs, amino acid mimetics, etc.). Unless otherwise indicated, naturally-occurring L-amino acids and D-amino acids are both represented by either conventional three-letter, or capitalized one-letter, amino acid designations of Table 1. In some embodiments, naturally-occurring L-amino acids are represented by either conventional three-letter, or capitalized one-letter, amino acid designations of Table 1. In some embodiments, D-amino acids, are represented by lower-case one-letter amino acid designations corresponding to one-letter designations of Table 1, i.e., g, a, l, m, f, w, k, q, e, s, p, v, i, c, y, h, r, n, d, and t. Table 1: Naturally-occurring amino acids G Glycine Gly P Proline Pro A Alanine Ala V Valine Val L Leucine Leu I Isoleucine Ile M Methionine Met C Cysteine Cys F Phenylalanine Phe Y Tyrosine Tyr W Tryptophan Trp H Histidine His K Lysine Lys R Arginine Arg Q Glutamine Gln N Asparagine Asn E Glutamic Acid Glu D Aspartic Acid Asp S Serine Ser T Threonine Thr The term “L-amino acid,” as used herein, refers to the “L” isomeric form of an amino acid, and conversely the term “D-amino acid” refers to the “D” isomeric form of an amino acid (e.g., (D)Asp or D-Asp; (D)Phe or D-Phe). Amino acid residues in the D isomeric form can be substituted for any L-amino acid residue, as long as the desired function is retained by the peptide. D-amino acids may be indicated as customary in lower case when referred to using single-letter abbreviations. For example, D-arginine can be represented as “arg” or “r.” Alternatively, a lower case “d” in front of an amino acid can be used to indicate that it is of the D isomeric form, for example D-lysine can be represented by dK. In the case of less common or non-naturally occurring amino acids, unless they are referred to by their full name (e.g., sarcosine, ornithine, etc.), frequently employed three- or four-character codes are employed for residues thereof, including, Sar or Sarc (sarcosine, i.e., N- methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dapa (2,3- diaminopropanoic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutanoic acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid). Amino acids of the D-isomeric form may be located at any of the positions in the IL- 23R inhibitors set forth herein (e.g., any of X3-X16 appearing in the molecule). In some embodiments, amino acids of the D-isomeric form may be located only at any one or more of X3, X5, X6, X8, X13, and optionally one additional position. In other embodiments, amino acids of the D-isomeric form may be located only at any one or more of X3, X8, X13, and optionally one additional position. In other embodiments, amino acids of the D-isomeric form may be located only at any one or more of X8, X13, and optionally one additional position. In other embodiments, amino acids of the D-isomeric form may be located only at X3 and optionally one additional position. In other embodiments, amino acids of the D-isomeric form may be located only at X3, and optionally two or three additional positions. In other embodiments, amino acids of the D-isomeric form may be located at only one or two of positions X3 to X16 appearing in the IL-23R inhibitors set forth herein. In other embodiments, amino acids of the D-isomeric form may be located at only three or four of positions X3 to X16 appearing in the IL-23R inhibitors set forth herein. For example, an IL-23R inhibitor set forth herein having only positions X3 to X15 present may have amino acids of the D-form present in three or four of those positions. In other embodiments, amino acids of the D-isomeric form may be located at only five or six of positions X3 to X16 appearing in the IL-23R inhibitors set forth herein. Peptides may be naturally occurring, synthetically produced, or recombinantly expressed. Peptides may also comprise additional groups modifying the amino acid chain, for example, functional groups added via post-translational modification. Examples of post-translation modifications include, but are not limited to, acetylation, alkylation (including, methylation), biotinylation, glutamylation, glycylation, glycosylation, isoprenylation, lipoylation, phosphopantetheinylation, phosphorylation, selenation, and C-terminal amidation. The term peptide also includes peptides comprising modifications of the amino terminus and/or the carboxy terminus. Modifications of the terminal amino group include, but are not limited to, des- amino, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications. Modifications of the terminal carboxy group include, but are not limited to, amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications (e.g., wherein lower alkyl is C1-C4 alkyl). The term peptide also includes modifications, such as but not limited to those described above, of amino acids falling between the amino and carboxy termini. As is clear to the skilled artisan, the peptide sequences disclosed herein are shown proceeding from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the C-terminus of the peptide. Among sequences disclosed herein are sequences incorporating either an “-OH” moiety or an “-NH2” moiety at the carboxy terminus (C-terminus) of the sequence. In such cases, and unless otherwise indicated, an “-OH” or an “-NH2” moiety at the C-terminus of the sequence indicates a hydroxy group or an amino group, corresponding to the presence of a carboxylic acid (COOH) or an amido (CONH2) group at the C-terminus, respectively. In each sequence of the disclosure, a C-terminal “-OH” moiety may be substituted for a C-terminal “-NH2” moiety, and vice-versa. The phrase “amino acid,” “amino acid residue,” or “residue” as used herein refers to an amino acid, a modified amino acid, an amino acid analog, or an amino acid mimetic that is incorporated into a peptide by an amide bond or an amide bond mimetic. Unless indicated otherwise the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions suggested by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature as set out in “Nomenclature of α-Amino Acids (Recommendations, 1974)” Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues employed in this specification and appended claims differ from those suggestions, they will be made clear to the reader. In sequences of amino acids that represent IL-23 inhibitors the individual amino acids are separated by a hyphen “-” or brackets e.g, lysine is shown as [K]. One of skill in the art will appreciate that certain amino acids and other chemical moieties are modified when bound to another molecule. For example, an amino acid side chain may be modified when it forms an intramolecular bridge with another amino acid side chain, e.g., one or more hydrogens may be removed or replaced by the bond. The term “therapeutically effective amount” or “pharmaceutically effective amount” means that amount of active peptide or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes preventing, treating or ameliorating the symptoms of a syndrome, disorder or disease being treated. The term “pharmaceutically acceptable” means approved or approvable by a regulatory agency of Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmcopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. “Composition” or “pharmaceutical composition” as used herein is intended to encompass a product comprising the specified active pharmaceutical ingredient (API) (i.e., a peptide of the present disclosure), which may include pharmaceutically acceptable excipients, carriers or diluents as described herein, such as in specified amounts defined throughout the disclosure. Compositions or pharmaceutical compositions of the present disclosure may be in different pharmaceutically acceptable forms, which may include, but are not limited to a liquid composition, a tablet or matrix composition, a capsule composition, etc.. When the composition is a tablet composition, the tablet may include, but is not limited to different layers two or more different phases, including an internal phase and an external phase that can comprise a core. The tablet composition can also include, but is not limited to one or more coatings. Provided are also pharmaceutically acceptable salts and tautomeric forms of the peptides described herein. A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of peptides represented by Formula (I) that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. It should possess the desired pharmacological activity of the parent compound. See, generally, G.S. Paulekuhn, et al., “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665–72, S.M. Berge, et al., “Pharmaceutical Salts”, J Pharm Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. A peptide of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. The IL-23R inhibitors of the present disclosure, pharmaceutically acceptable salts, and/or other forms thereof may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms of the IL-23R inhibitors of the present disclosure. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where compounds are represented in their chiral form, it is understood that the aspect encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the aspect is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s). “Racemates” refers to a mixture of enantiomers. The mixture can include equal or unequal amounts of each enantiomer. “Stereoisomer” and “stereoisomers” refer to compounds that differ in the chirality of one or more stereo centers. Stereoisomers include enantiomers and diastereomers. The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992). “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A “racemic” mixture is a 1:1 mixture of a pair of enantiomers. A “scalemic” mixture of enantiomers is mixture of enantiomers at a ratio other than 1:1. “Tautomer” refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- and a ring =N- such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. The term “administering” with respect to the methods of the present disclosure, means a method for therapeutically or prophylactically preventing, treating or ameliorating a syndrome, disorder or disease as described herein by using a compound of the disclosure, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof. Such methods include administering a therapeutically effective amount of a peptide of the disclosure, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof, at different times during the course of a therapy or concurrently or sequentially as a combination therapy. “Patient” or “subject”, which are used interchangably, refer to a living organism, preferably a mammal, most preferably a human, whom will be or has been treated by a method according to an embodiment of the application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, etc., more preferably a human. As used herein, the term “treatment” or “treating,” is defined as the application or administration of a therapeutic agent, i.e., a compound of the present disclosure (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disorder or disease as described herein, a symptom thereof; or the potential to develop such disorder or disease, where the purpose of the application or administration is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder or disease, its symptoms, or the potential to develop said disorder or disease. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics. As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly or conventionally understood by one of ordinary skill in the art. In the chemical arts a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. A dashed line indicates an optional bond. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or the point at which it is attached to the remainder of the molecule. For instance, the group “-SO2CH2- ” is equivalent to “-CH2SO2-” and both may be connected in either direction. Similarly, an “arylalkyl” group, for example, may be attached to the remainder of the molecule at either an aryl or an alkyl portion of the group. A prefix such as “Cu-v” or (Cu-Cv) indicates that the following group has from u to v carbon atoms. For example, “C1-6alkyl” and “C1-C6 alkyl” both indicate that the alkyl group has from 1 to 6 carbon atoms. Furthermore, it is intended that within the scope of the present invention, any element, in particular when mentioned in relation to a peptide of the disclosure, or pharmaceutically acceptable salt thereof, shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope 1H, 2H (i.e., deuterium or D), and 3H (i.e., tritium or T). In some embodiments, the compounds described herein include a 2H (i.e., deuterium) isotope. By way of example, the group denoted -C(1-6)alkyl includes not only -CH3, but also CD3; not only CH2CH3, but also CD2CD3, etc. Similarly, references to carbon and oxygen include within their scope respectively 12C, 13C and 14C and 15O and 16O and 17O and 18O. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of the disclsoure may include a radioactive isotope selected from the group comprising 3H, 11C, 18F, 35S, 122I, 123I, 125I, 131I, 75Br, 76Br, 77Br and 82Br. Preferably, the radioactive isotope is selected from the group of 3H, 11C and 18F. Abbreviation, “(V/V)” refers to the phrase “volume for volume”, i.e., the proportion of a particular substance within a mixture, as measured by volume or a volume amount of a component of the composition disclosed herein relative to the total volume amount of the composition. Accordingly, the quantity is unit less and represents a volume percentage amount of a component relative to the total volume of the composition. For example, a 2% (V/V) solvent mixture can indicate 2 mL of one solvent is present in 100 mL of the solvent mixture. Systemic routes of administration as conventionally understood in the medicinal or pharmaceutical arts, refer to or are defined as a route of administration of drug, a pharmaceutical composition or formulation, or other substance into the circulatory system so that various body tissues and organs are exposed to the drug, formulation or other substance. As conventionally understood in the art, administration can take place orally (where drug or oral preparations are taken by mouth, and absorbed via the gastrointestinal tract), via enteral administration (absorption of the drug also occurs through the gastrointestinal tract) or parenteral administration (generally injection, infusion, or implantation, etc. “Bioavailability” refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. Bioavailability of a drug could be impacted by the factors such as properties of the dosage form and properties of the drug. “Digestive tract tissue” as used herein refers to all the tissues that comprise the organs of the alimentary canal. For example only, and without limitation, “digestive tract tissue” includes tissues of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus. Compounds The present disclosure provides a peptide inhibitor of interleukin-23 receptor. In one aspect, the present disclosure provides a peptide of Formula (I), comprising the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I), or a pharmaceutically acceptable salt thereof, wherein: X3-X4-X5-X6 is selected from the group consisting of: X4–N–T, dR–X4–N–T, X4–dN–aMeT, X4–N–aMeT, dA–dN–dT, X4–b3hN–T, X4–N–b3hT, dE–X4–N–T, dR–X4–A–A, dR–X4–A–T, dR–X4–dN–dT, dR–X4–dN–T, dR–X4–N–A, dR–X4–N–dT, and R–X4–N–T, wherein X4 is an amino acid that is optionally linked to the amino acid at X9; X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–K(Ac)–X9–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–X9–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X9–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X9–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–X9–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–X9–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–X9–AEF–2Nal–THP, 7MeW–A–X9–A–2Nal–THP, 7MeW–A–X9–AEF(G)–2Nal–THP, 7MeW–A–X9–AEF–2Nal–THP, 7MeW–b3hK–X9–AEF–2Nal–THP, 7MeW–b3hQ–X9–AEF–2Nal–THP, 7MeW–b3hQ–X9–AEF–b3hF–THP, 7MeW–dK(Ac)–X9–AEF–2Nal–THP, 7MeW–K(Ac)–X9–A–2Nal–THP, 7MeW–K(Ac)–X9–A–A–THP, 7MeW–K(Ac)–X9–AEF–2Nal–A, 7MeW–K(Ac)–X9–AEF–2Nal–Aib, 7MeW–K(Ac)–X9–AEF–b3hF–THP, 7MeW–K(Ac)–X9–APF–2Nal–THP, 7MeW–K(Ac)–X9–b3hY–2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–X9–YCF2H–2Nal–THP, A–A–X9–A–A–THP, A–A–X9–AEF–2Nal–THP, A–K(Ac)–X9–AEF–A–THP, b3hW–K(Ac)–X9–AEF–2Nal–THP, b3hW–K(Ac)–X9–AEF–b3hF–THP, b3hW–K(Ac)–X9–b3hY–2Nal–THP, d7MeW–dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–X9–AEF–2Nal–THP, F–K(Ac)–X9–AEF–F–THP, L–K(Ac)–X9–AEF–2Nal–THP, L–K(Ac)–X9–AEF–L–THP, 7MeW–K(Ac)–X9–AEF–F–THP, and 7MeW–K(Ac)–X9–AEF–L–THP, wherein X9 is and amino acid that is optionally linked to the amino acid at X4; X13-X14-X15-X16 is selected from the group consisting of: E–N–3Pya–Sar, K(Ac)–N–3Pya–Sar, A–N–3Pya–Sar, b3hE–N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N–L–Sar, K(Ac)–N–5MePyridinAla–Sar, and R–N–3Pya–Sar; wherein no more than two of the following are true: X3-X4-X5-X6 is Abu–N–T, X3-X4-X5-X6 is C–N–T, X3-X4-X5-X6 is Pen–N–T, X3-X4-X5-X6 is dR–Abu–N–T, X3-X4-X5-X6 is dR–C–N–T, X3-X4-X5-X6 is dR–Pen–N–T, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–C–AEF–2Nal–THP, X13-X14-X15-X16 is E–N–3Pya–Sar, and X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar. In some embodiments, the present disclosure provides a peptide of Formula (I), comprising the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I), or a pharmaceutically acceptable salt thereof, wherein: X3-X4-X5-X6 is selected from the group consisting of: X4–N–T, dR–X4–N–T, X4–dN–aMeT, X4–N–aMeT, dA–dN–dT, X4–b3hN–T, X4–N–b3hT, dE–X4–N–T, dR–X4–A–A, dR–X4–A–T, dR–X4–dN–dT, dR–X4–dN–T, dR–X4–N–A, dR–X4–N–dT, and R–X4–N–T, wherein X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–K(Ac)–X9–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–X9–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X9–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X9–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–X9–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–X9–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–X9–AEF–2Nal–THP, 7MeW–A–X9–A–2Nal–THP, 7MeW–A–X9–AEF(G)–2Nal–THP, 7MeW–A–X9–AEF–2Nal–THP, 7MeW–b3hK–X9–AEF–2Nal–THP, 7MeW–b3hQ–X9–AEF–2Nal–THP, 7MeW–b3hQ–X9–AEF–b3hF–THP, 7MeW–dK(Ac)–X9–AEF–2Nal–THP, 7MeW–K(Ac)–X9–A–2Nal–THP, 7MeW–K(Ac)–X9–A–A–THP, 7MeW–K(Ac)–X9–AEF–2Nal–A, 7MeW–K(Ac)–X9–AEF–2Nal–Aib, 7MeW–K(Ac)–X9–AEF–b3hF–THP, 7MeW–K(Ac)–X9–APF–2Nal–THP, 7MeW–K(Ac)–X9–b3hY–2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–X9–YCF2H–2Nal–THP, A–A–X9–A–A–THP, A–A–X9–AEF–2Nal–THP, A–K(Ac)–X9–AEF–A–THP, b3hW–K(Ac)–X9–AEF–2Nal–THP, b3hW–K(Ac)–X9–AEF–b3hF–THP, b3hW–K(Ac)–X9–b3hY–2Nal–THP, d7MeW–dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–X9–AEF–2Nal–THP, F–K(Ac)–X9–AEF–F–THP, L–K(Ac)–X9–AEF–2Nal–THP, L–K(Ac)–X9–AEF–L–THP, 7MeW–K(Ac)–X9–AEF–F–THP, and 7MeW–K(Ac)–X9–AEF–L–THP, wherein X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X13-X14-X15-X16 is selected from the group consisting of: E–N–3Pya–Sar, K(Ac)–N–3Pya–Sar, A–N–3Pya–Sar, b3hE–N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N–L–Sar, K(Ac)–N–5MePyridinAla–Sar, and R–N–3Pya–Sar; wherein no more than two of the following are true: X3-X4-X5-X6 is Abu–N–T, X3-X4-X5-X6 is C–N–T, X3-X4-X5-X6 is Pen–N–T, X3-X4-X5-X6 is dR–Abu–N–T, X3-X4-X5-X6 is dR–C–N–T, X3-X4-X5-X6 is dR–Pen–N–T, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–C–AEF–2Nal–THP, X13-X14-X15-X16 is E–N–3Pya–Sar, and X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar; and wherein the 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra at X4 is optionally linked to the aMeC, aG, C, D, E, hE, Pen, or Dap(N3) at X9. In some embodiments, no more than two of the following are true: X3-X4-X5-X6 is Abu–N–T, X3-X4-X5-X6 is aMeC–N–T, X3-X4-X5-X6 is C–N–T, X3-X4-X5-X6 is Pen–N–T, X3-X4-X5-X6 is dR–Abu–N–T, X3-X4-X5-X6 is dR–aMeC–N–T, X3-X4-X5-X6 is dR–C–N–T, X3-X4-X5-X6 is dR–Pen–N–T, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–C–AEF–2Nal–THP, X13-X14-X15-X16 is E–N–3Pya–Sar, and X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar. In some embodiments, no more than two of the following are true: X3-X4-X5-X6 is X4–N–T, X3-X4-X5-X6 is dR–X4–N–T, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–THP, X13-X14-X15-X16 is E–N–3Pya–Sar, and X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar. In some embodiments, no more than one of the following is true: X3-X4-X5-X6 is X4–N–T, X3-X4-X5-X6 is aMeC–N–T, X3-X4-X5-X6 is C–N–T, X3-X4-X5-X6 is Pen–N–T, X3-X4-X5-X6 is dR–Abu–N–T, X3-X4-X5-X6 is dR–aMeC–N–T, X3-X4-X5-X6 is dR–C–N–T, X3-X4-X5-X6 is dR–Pen–N–T, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–C–AEF–2Nal–THP, X13-X14-X15-X16 is E–N–3Pya–Sar, and X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar. In some embodiments, no more than one of the following are true: X3-X4-X5-X6 is X4–N–T, X3-X4-X5-X6 is dR–X4–N–T, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–THP, X13-X14-X15-X16 is E–N–3Pya–Sar, and X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar. In some embodiments, X4 is 4AminoPro, Abu, aG, aMeC, Api, C, D, Dap, Dab, E, hA, hE, hK, K, Orn, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), Pra, R5H, R5Me, S5H, or S5Me. In some embodiments, X4 is Dap, Dab, hK, K, or Orn. In some embodiments, X4 is Api, D, E, or hE. In some embodiments, X4 is aG, R5H, R5Me, S5H, or S5Me. In some embodiments, X4 is 4AminoPro, aG, Dap, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra. In some embodiments, X4 is Abu, aMeC, C, Pen, Pen(oXyl), Pen(mXyl), or Pen(pXyl). In some embodiments, X4 is Abu, aMeC, C, or Pen. In some embodiments, X4 is Abu, C, or Pen. In some embodiments, X4 is Abu or Pen. In some embodiments, X4 is 4AminoPro. In some embodiments, X4 is 4RAminoPro. In some embodiments, X4 is 4SAminoPro. In some embodiments, X4 is Abu. In some embodiments, X4 is aG. In some embodiments, X4 is aMeC. In some embodiments, X4 is Api. In some embodiments, X4 is C. In some embodiments, X4 is D. In some embodiments, X4 is Dap. In some embodiments, X4 is Dab. In some embodiments, X4 is E. In some embodiments, X4 is hA. In some embodiments, X4 is hE. In some embodiments, X4 is hK. In some embodiments, X4 is K. In some embodiments, X4 is Orn. In some embodiments, X4 is Pen. In some embodiments, X4 is Pen(oXyl). In some embodiments, X4 is Pen(mXyl). In some embodiments, X4 is Pen(pXyl). In some embodiments, X4 is Pra. In some embodiments, X4 is R5H. In some embodiments, X4 is R5Me. In some embodiments, X4 is S5H. In some embodiments, X4 isS5Me. In some embodiments, X9 is aMeC, aG, Api, C, D, Dab, Dap, E, hA, hE, hK, K, Orn, Pen, Dap(N3), R5H, R5Me, S5H, or S5Me. In some embodiments, X9 is Dap, Dab, hK, K, or Orn. In some embodiments, X9 is Api, D, E, or hE. In some embodiments, X9 is aG, R5H, R5Me, S5H, or S5Me. In some embodiments, X9 is aG, D, E, hE, or Dap(N3). In some embodiments, X9 is aMeC, C, or Pen. In some embodiments, X9 is aMeC or Pen. In some embodiments, X9 is aMeC. In some embodiments, X9 is aG. In some embodiments, X9 is Api. In some embodiments, X9 is C. In some embodiments, X9 is D. In some embodiments, X9 is Dab. In some embodiments, X9 is Dap. In some embodiments, X9 is E. In some embodiments, X9 is hA. In some embodiments, X9 is hE. In some embodiments, X9 is hK. In some embodiments, X9 is K. In some embodiments, X9 is Orn. In some embodiments, X9 is Pen. In some embodiments, X9 is Dap(N3). In some embodiments, X9 is R5H. In some embodiments, X9 is R5Me. In some embodiments, X9 is S5H. In some embodiments, X9 is S5Me. In some embodiments, X4 is Abu, aMeC, C, or Pen, and X9 is aMeC, C, or Pen. In some embodiments, X4 is Abu and X9 is C. In some embodiments, X4 is Abu and X9 is aMeC. In some embodiments, X4 is Abu and X9 is Pen. In some embodiments, X4 is C and X9 is C. In some embodiments, X4 is C and X9 is aMeC. In some embodiments, X4 is C and X9 is Pen. In some embodiments, X4 is Pen and X9 is C. In some embodiments, X4 is Pen and X9 is aMeC. In some embodiments, X4 is Pen and X9 is Pen. In some embodiments, X4 is aMeC and X9 is C. In some embodiments, X4 is aMeC and X9 is aMeC. In some embodiments, X4 is aMeC and X9 is Pen. In some embodiments, X4 is Pen(oXyl) and X9 is C. In some embodiments, X4 is Pen(oXyl) and X9 is aMeC. In some embodiments, X4 is Pen(oXyl) and X9 is Pen. In some embodiments, X4 is Pen(mXyl) and X9 is C. In some embodiments, X4 is Pen(mXyl) and X9 is aMeC. In some embodiments, X4 is Pen(mXyl) and X9 is Pen. In some embodiments, X4 is Pen(pXyl) and X9 is C. In some embodiments, X4 is Pen(pXyl) and X9 is aMeC. In some embodiments, X4 is Pen(pXyl) and X9 is Pen. In some embodiments, X4 is 4AminoPro and X9 is D. In some embodiments, X4 is 4AminoPro and X9 is E. In some embodiments, X4 is 4AminoPro and X9 is hE. In some embodiments, X4 Dap, Dab, hK, K, or Orn, and X9 is Api, D, E, or hE. In some embodiments, X4 is Dap and X9 is Api, D, E, or hE. In some embodiments, X4 is Dab and X9 is Api, D, E, or hE. In some embodiments, X4 is hK and X9 is Api, D, E, or hE. In some embodiments, X4 is K and X9 is Api, D, E, or hE. In some embodiments, X4 is Orn and X9 is Api, D, E, or hE. In some embodiments, X4 Dap, Dab, hK, K, or Orn, and X9 is Api. In some embodiments, X4 Dap, Dab, hK, K, or Orn, and X9 is D. In some embodiments, X4 Dap, Dab, hK, K, or Orn, and X9 is E. In some embodiments, X4 Dap, Dab, hK, K, or Orn, and X9 is hE. In some embodiments, X4 is Api, D, E, or hE and X9 is Dap, Dab, hK, K, or Orn. In some embodiments, X4 is Api and X9 is Dap, Dab, hK, K, or Orn. In some embodiments, X4 is D and X9 is Dap, Dab, hK, K, or Orn. In some embodiments, X4 is E and X9 is Dap, Dab, hK, K, or Orn. In some embodiments, X4 is hE and X9 is Dap, Dab, hK, K, or Orn. In some embodiments, X4 is Api, D, E, or hE and X9 is Dap. In some embodiments, X4 is Api, D, E, or hE and X9 is Dab. In some embodiments, X4 is Api, D, E, or hE and X9 is hK. In some embodiments, X4 is Api, D, E, or hE and X9 is K. In some embodiments, X4 is Api, D, E, or hE and X9 is Orn. In some embodiments, X4 is Dap and X9 is D. In some embodiments, X4 is Dap and X9 is E. In some embodiments, X4 is Dap and X9 is hE. In some embodiments, X4 is aG, R5H, R5Me, S5H, or S5Me and X9 is aG, R5H, R5Me, S5H, or S5Me. In some embodiments, X4 is R5H, R5Me, S5H, or S5Me and X9 is R5H, R5Me, S5H, or S5Me. In some embodiments, X4 is Pra and X9 is Dap(N3). In some embodiments, X4 is aG and X9 is aG. In some embodiments, X4 is hA and X9 is hA. In some embodiments, the peptide comprises a linker between the α-carbon of X4 and the α-carbon of X9. In some embodiments, the linker is less than 24 Angstroms (Å) in length. In some embodiments, the linker is less than 20 Å in length. In some embodiments, the linker is between 4 Å and 24 Å in length. In some embodiments, the linker is between 4 Å and 20 Å in length. In some embodiments, the linker is between 10 Å and 24 Å in length. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 18 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 2 and 16 carbon atoms. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 16 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, S, and H atoms, and comprises between 4 and 16 atoms selected from C and S. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 2 and 14 carbon atoms. In some embodiments, the linker consists of C, S, and H atoms, and comprises between 2 and 14 carbon atoms. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 14 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 12 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 2 and 12 carbon atoms. In some embodiments, the peptide is cyclized via a linkage between two amino acid residues (e.g., at X4 and X9) having a structure selected from the following:
In some embodiments, the peptide is cyclized via a linkage between two amino acid residues (e.g., at X4 and X9) having a structure selected from the following:
In some embodiments, the peptide is cyclized via a linkage between the residues at X4
In some embodiments, the peptide is cyclized via a linkage between the residues at X4 In some embodiments, the peptide is cyclized via a linkage between the residues at X4 and X9 having a structure selected from the following:
In some embodiments, the peptide is cyclized via a linkage between the residues at X4 and X9 having a structure selected from the following: In some embodiments, the peptide is cyclized via a linkage between the residues at X4 and X9 having the following structure: Pen – Pen. In some embodiments, the present disclosure provides a peptide of Formula (I), comprising the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I), or a pharmaceutically acceptable salt thereof, wherein: X3-X4-X5-X6 is selected from the group consisting of: Abu–N–T, C–N–T, Pen–N–T, dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, Pen–N–b3hT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR–Pen–dN–T, dR–Pen–N–A, dR–Pen–N–dT, and R–Pen–N–T; X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW–dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, A–A–Pen–A–A–THP, A–A–Pen–AEF–2Nal–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, d7MeW–dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–2Nal–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, and 7MeW–K(Ac)–Pen–AEF–L–THP, X13-X14-X15-X16 is selected from the group consisting of: E–N–3Pya–Sar, K(Ac)–N–3Pya–Sar, A–N–3Pya–Sar, b3hE–N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N–L–Sar, K(Ac)–N–5MePyridinAla–Sar, and R–N–3Pya–Sar; wherein no more than two of the following are true: X3-X4-X5-X6 is Abu–N–T, X3-X4-X5-X6 is C–N–T, X3-X4-X5-X6 is Pen–N–T, X3-X4-X5-X6 is dR–Abu–N–T, X3-X4-X5-X6 is dR–C–N–T, X3-X4-X5-X6 is dR–Pen–N–T, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–C–AEF–2Nal–THP, X13-X14-X15-X16 is E–N–3Pya–Sar, and X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar; and wherein the Abu, C, or Pen in X3-X4-X5-X6 is optionally linked to the aMeC, C, or Pen in X7-X8-X9-X10-X11-X12 via a disulfide or thioether bond. In some embodiments, the peptide comprises an amino acid sequence selected from the group consisting of: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I-A1), X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (I-A2), and R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (I-A3), or a pharmaceutically acceptable salt thereof. R1 represents the N-terminal end of the peptide, which may be, for example, a hydrogen or a chemical moiety or functional group substituted on the amino group (e.g., an acetate group). Similarly, R2 represents the carboxyl end, which may be, for example the OH of the carboxyl or a chemical moiety or functional group attached thereto or substituted for the OH group (e.g., an amino group to give a terminal amide, e.g., -CONH2); In some embodiments, R1 is MeCO or EtCO, and R2 is CONH2. In some embodiments, the peptide comprises an amino acid sequence of Formula (I-A1): R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I-A1), or a pharmaceutically acceptable salt thereof, wherein R1 is MeCO or EtCO. In some embodiments, the peptide comprises an amino acid sequence of Formula (I-A2): X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (I-A2), or a pharmaceutically acceptable salt thereof, wherein R2 is CONH2. In some embodiments, the peptide comprises an amino acid sequence of Formula (I-A3): R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (I-A3), or a pharmaceutically acceptable salt thereof, wherein R1 is MeCO or EtCO, and R2 is CONH2. In some embodiments, no more than one of the following is true: X3-X4-X5-X6 is Abu–N–T, X3-X4-X5-X6 is C–N–T, X3-X4-X5-X6 is Pen–N–T, X3-X4-X5-X6 is dR–Abu–N–T, X3-X4-X5-X6 is dR–C–N–T, X3-X4-X5-X6 is dR–Pen–N–T, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–C–AEF–2Nal–THP, X13-X14-X15-X16 is E–N–3Pya–Sar, and X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar. In some embodiments, X3-X4-X5-X6 is X4–dN–aMeT, X4–N–aMeT, dA–dN–dT, X4– b3hN–T, X4–N–b3hT, dE–X4–N–T, dR–X4–A–A, dR–X4–A–T, dR–X4–dN–dT, dR–X4–dN–T, dR–X4–N–A, dR–X4–N–dT, or R–X4–N–T. In some embodiments, X3-X4-X5-X6 is Abu–N–T, C–N–T, dR–Abu–N–T, dR–C–N–T, Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, Pen–N–b3hT, dE–Pen–N–T, dR– Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR–Pen–dN–T, dR–Pen–N–A, dR–Pen–N–dT, or R– Pen–N–T. In some embodiments, X3-X4-X5-X6 is Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, Pen–N–b3hT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR– Pen–dN–T, dR–Pen–N–A, dR–Pen–N–dT, or R–Pen–N–T. In some embodiments, X3-X4-X5-X6 is X4–N–T, dR–X4–N–T, X4–dN–aMeT, X4–N– aMeT, dA–dN–dT, X4–b3hN–T, X4–N–b3hT, dE–X4–N–T, dR–X4–A–A, dR–X4–A–T, or dR– X4–N–A. In some embodiments, X3-X4-X5-X6 is Abu–N–T, C–N–T, Pen–N–T, dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, Pen–N– b3hT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, or dR–Pen–N–A. In some embodiments, X3-X4-X5-X6 is X4–N–T, X4–dN–aMeT, X4–N–aMeT, dA–dN– dT, X4–b3hN–T, or X4–N–b3hT. In some embodiments, X3-X4-X5-X6 is Abu–N–T, C–N–T, Pen–N–T, Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, or Pen–N–b3hT. In some embodiments, X3-X4-X5-X6 is dR–X4–N–T, dA–dN–dT, dE–X4–N–T, dR–X4– A–A, dR–X4–A–T, dR–X4–dN–dT, dR–X4–dN–T, dR–X4–N–A dR–X4–N–dT, or R–X4–N–T. In some embodiments, X3-X4-X5-X6 is dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, dA– dN–dT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR–Pen–dN–T, dR–Pen– N–A, dR–Pen–N–dT, and R–Pen–N–T. In some embodiments, X3-X4-X5-X6 is Pen–N–T, dR–Pen–N–T, Pen–b3hN–T, Pen–N– b3hT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR–Pen–dN–T, dR–Pen– N–A, dR–Pen–N–dT, and R–Pen–N–T. In some embodiments, X3-X4-X5-X6 is Abu–N–T, C–N–T, dR–Abu–N–T, dR–C–N–T, Abu–dN–aMeT, Abu–N–aMeT, and dA–dN–dT. In some embodiments, X3-X4-X5-X6 is X4–N–T, dR–X4–N–T, X4–N–aMeT, X4–N– b3hT, dE–X4–N–T, dR–X4–N–A, dR–X4–N–dT, or R–X4–N–T. In some embodiments, X3-X4-X5-X6 is Abu–N–T, C–N–T, Pen–N–T, dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, Abu–N–aMeT, Pen–N–b3hT, dE–Pen–N–T, dR–Pen–N–A, dR– Pen–N–dT, or R–Pen–N–T. In some embodiments, X3-X4-X5-X6 is X4–dN–aMeT, dA–dN–dT, X4–b3hN–T, dR–X4– A–A, dR–X4–A–T, dR–X4–dN–dT, or dR–X4–dN–T. In some embodiments, X3-X4-X5-X6 is Abu–dN–aMeT, dA–dN–dT, Pen–b3hN–T, dR– Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, or dR–Pen–dN–T. In some embodiments, X3-X4-X5-X6 is X4–N–T, dR–X4–N–T, X4–b3hN–T, dE–X4–N–T, dR–X4–A–T, dR–X4–dN–T, or R–X4–N–T. In some embodiments, X3-X4-X5-X6 is Abu–N–T, C–N–T, Pen–N–T, dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, Pen–b3hN–T, dE–Pen–N–T, dR–Pen–A–T, dR–Pen–dN–T, or R– Pen–N–T. In some embodiments, X3-X4-X5-X6 is X4–dN–aMeT, X4–N–aMeT, dA–dN–dT, X4–N– b3hT, dR–X4–A–A, dR–X4–dN–dT, dR–X4–N–A, or dR–X4–N–dT. In some embodiments, X3-X4-X5-X6 is Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–N–b3hT, dR–Pen–A–A, dR–Pen–dN–dT, dR–Pen–N–A, or dR–Pen–N–dT. In some embodiments, X3-X4-X5-X6 is X4–N–T. In some embodiments, X3-X4-X5-X6 is dR–X4–N–T. In some embodiments, X3-X4-X5-X6 is X4–dN–aMeT. In some embodiments, X3- X4-X5-X6 is X4–N–aMeT. In some embodiments, X3-X4-X5-X6 is dA–dN–dT. In some embodiments, X3-X4-X5-X6 is X4–b3hN–T. In some embodiments, X3-X4-X5-X6 is X4–N–b3hT. In some embodiments, X3-X4-X5-X6 is dE–X4–N–T. In some embodiments, X3-X4-X5-X6 is dR– X4–A–A. In some embodiments, X3-X4-X5-X6 is dR–X4–A–T. In some embodiments, X3-X4-X5- X6 is dR–X4–dN–dT. In some embodiments, X3-X4-X5-X6 is dR–X4–dN–T. In some embodiments, X3-X4-X5-X6 is dR–X4–N–A. In some embodiments, X3-X4-X5-X6 is dR–X4–N– dT,. In some embodiments, X3-X4-X5-X6 is R–X4–N–T. In some embodiments, X3-X4-X5-X6 is Abu–N–T. In some embodiments, X3-X4-X5-X6 is C–N–T. In some embodiments, X3-X4-X5-X6 is Pen–N–T. In some embodiments, X3-X4-X5-X6 is dR–Abu–N–T. In some embodiments, X3-X4-X5-X6 is dR–C–N–T. In some embodiments, X3- X4-X5-X6 is dR–Pen–N–T. In some embodiments, X3-X4-X5-X6 is Abu–dN–aMeT. In some embodiments, X3-X4-X5-X6 is Abu–N–aMeT. In some embodiments, X3-X4-X5-X6 is dA–dN– dT. In some embodiments, X3-X4-X5-X6 is Pen–b3hN–T. In some embodiments, X3-X4-X5-X6 is Pen–N–b3hT. In some embodiments, X3-X4-X5-X6 is dE–Pen–N–T. In some embodiments, X3- X4-X5-X6 is dR–Pen–A–A. In some embodiments, X3-X4-X5-X6 is dR–Pen–A–T. In some embodiments, X3-X4-X5-X6 is dR–Pen–dN–dT. In some embodiments, X3-X4-X5-X6 is dR–Pen– dN–T. In some embodiments, X3-X4-X5-X6 is dR–Pen–N–A. In some embodiments, X3-X4-X5- X6 is dR–Pen–N–dT. In some embodiments, X3-X4-X5-X6 is R–Pen–N–T. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3(1NMepip)pyraz)W–K(Ac)–X9– AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X9–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9– AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X9– AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X9–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W– K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–X9–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–X9–AEF–2Nal– THP, 7(7(2OMeQuin))W–K(Ac)–X9–AEF–2Nal–THP, 7MeW–A–X9–A–2Nal–THP, 7MeW– A–X9–AEF(G)–2Nal–THP, 7MeW–A–X9–AEF–2Nal–THP, 7MeW–b3hK–X9–AEF–2Nal– THP, 7MeW–b3hQ–X9–AEF–2Nal–THP, 7MeW–b3hQ–X9–AEF–b3hF–THP, 7MeW– dK(Ac)–X9–AEF–2Nal–THP, 7MeW–K(Ac)–X9–A–2Nal–THP, 7MeW–K(Ac)–X9–A–A–THP, 7MeW–K(Ac)–X9–AEF–2Nal–A, 7MeW–K(Ac)–X9–AEF–2Nal–Aib, 7MeW–K(Ac)–X9– AEF–b3hF–THP, 7MeW–K(Ac)–X9–APF–2Nal–THP, 7MeW–K(Ac)–X9–b3hY–2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–X9–YCF2H–2Nal–THP, A–A–X9–A–A–THP, A–A–X9–AEF–2Nal–THP, A– K(Ac)–X9–AEF–A–THP, b3hW–K(Ac)–X9–AEF–2Nal–THP, b3hW–K(Ac)–X9–AEF–b3hF– THP, b3hW–K(Ac)–X9–b3hY–2Nal–THP, d7MeW–dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)– X9–AEF–2Nal–THP, F–K(Ac)–X9–AEF–F–THP, L–K(Ac)–X9–AEF–2Nal–THP, L–K(Ac)– X9–AEF–L–THP, 7MeW–K(Ac)–X9–AEF–F–THP, or 7MeW–K(Ac)–X9–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal– THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF– 2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)– Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal– THP, 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW– A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal– THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW– dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen– A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–A, 7MeW– K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, 7MeW–K(Ac)–Pen–APF– 2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal– THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, A– A–Pen–A–A–THP, A–A–Pen–AEF–2Nal–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)– Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, b3hW–K(Ac)–Pen–b3hY–2Nal– THP, d7MeW–dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F–K(Ac)–Pen– AEF–F–THP, L–K(Ac)–Pen–AEF–2Nal–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)– Pen–AEF–F–THP, or 7MeW–K(Ac)–Pen–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3(1NMepip)pyraz)W–K(Ac)–Pen– AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)– aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W– K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen– AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)– Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP, 7MeW–A–Pen–A– 2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW– b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF– b3hF–THP, 7MeW–dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–AEF– 2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, 7MeW– K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen– F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen– YCF2H–2Nal–THP, A–A–Pen–A–A–THP, A–A–Pen–AEF–2Nal–THP, A–K(Ac)–Pen–AEF– A–THP, b3hW–K(Ac)–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, b3hW– K(Ac)–Pen–b3hY–2Nal–THP, d7MeW–dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–Pen–AEF– 2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–2Nal–THP, L–K(Ac)–Pen–AEF– L–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, or 7MeW–K(Ac)–Pen–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–THP, 7MeW–A–X9–A–2Nal–THP, 7MeW–A–X9–AEF(G)–2Nal–THP, 7MeW–A–X9–AEF–2Nal– THP, 7MeW–b3hK–X9–AEF–2Nal–THP, 7MeW–b3hQ–X9–AEF–2Nal–THP, 7MeW–b3hQ– X9–AEF–b3hF–THP, 7MeW–dK(Ac)–X9–AEF–2Nal–THP, 7MeW–K(Ac)–X9–A–2Nal–THP, 7MeW–K(Ac)–X9–A–A–THP, 7MeW–K(Ac)–X9–AEF–2Nal–A, 7MeW–K(Ac)–X9–AEF– 2Nal–Aib, 7MeW–K(Ac)–X9–AEF–b3hF–THP, 7MeW–K(Ac)–X9–APF–2Nal–THP, 7MeW– K(Ac)–X9–b3hY–2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–X9– F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–X9–YCF2H–2Nal–THP, 7MeW–K(Ac)–X9–AEF–F– THP, or 7MeW–K(Ac)–X9–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7MeW–A–Pen–A– 2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW– b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF– b3hF–THP, 7MeW–dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–AEF– 2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, 7MeW– K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen– F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen– YCF2H–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, or 7MeW–K(Ac)–Pen–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3(1NMepip)pyraz)W–K(Ac)–X9– AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X9–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9– AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X9– AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X9–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W– K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–X9–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–X9–AEF–2Nal– THP, 7(7(2OMeQuin))W–K(Ac)–X9–AEF–2Nal–THP, A–A–X9–A–A–THP, A–A–X9–AEF– 2Nal–THP, A–K(Ac)–X9–AEF–A–THP, b3hW–K(Ac)–X9–AEF–2Nal–THP, b3hW–K(Ac)– X9–AEF–b3hF–THP, b3hW–K(Ac)–X9–b3hY–2Nal–THP, d7MeW–dK(Ac)–dA–dY–d2Nal– THP, F–K(Ac)–X9–AEF–2Nal–THP, F–K(Ac)–X9–AEF–F–THP, L–K(Ac)–X9–AEF–2Nal– THP, or L–K(Ac)–X9–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3(1NMepip)pyraz)W–K(Ac)–Pen– AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)– aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W– K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen– AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)– Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP, A–A–Pen–A–A–THP, A–A–Pen–AEF–2Nal–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–2Nal– THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, d7MeW– dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L– K(Ac)–Pen–AEF–2Nal–THP, or L–K(Ac)–Pen–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–X9–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X9–AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF(G)– 2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X9–AEF– 2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W – K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–X9–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–X9–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–X9–AEF–2Nal– THP, 7MeW–K(Ac)–X9–A–2Nal–THP, 7MeW–K(Ac)–X9–A–A–THP, 7MeW–K(Ac)–X9– AEF–2Nal–A, 7MeW–K(Ac)–X9–AEF–2Nal–Aib, 7MeW–K(Ac)–X9–AEF–b3hF–THP, 7MeW–K(Ac)–X9–APF–2Nal–THP, 7MeW–K(Ac)–X9–b3hY–2Nal–THP, 7MeW–K(Ac)–X9– F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–X9– YCF2H–2Nal–THP, A–K(Ac)–X9–AEF–A–THP, b3hW–K(Ac)–X9–AEF–2Nal–THP, b3hW– K(Ac)–X9–AEF–b3hF–THP, b3hW–K(Ac)–X9–b3hY–2Nal–THP, F–K(Ac)–X9–AEF–2Nal– THP, F–K(Ac)–X9–AEF–F–THP, L–K(Ac)–X9–AEF–2Nal–THP, L–K(Ac)–X9–AEF–L–THP, 7MeW–K(Ac)–X9–AEF–F–THP, or 7MeW–K(Ac)–X9–AEF–L–THP, In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen– AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W– K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF– 2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen– AEF–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW– K(Ac)–Pen–AEF–2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–AEF– b3hF–THP, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen– AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–2Nal–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, or 7MeW–K(Ac)–Pen–AEF– L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–A–X9–A–2Nal–THP, 7MeW– A–X9–AEF(G)–2Nal–THP, 7MeW–A–X9–AEF–2Nal–THP, 7MeW–b3hK–X9–AEF–2Nal– THP, 7MeW–b3hQ–X9–AEF–2Nal–THP, 7MeW–b3hQ–X9–AEF–b3hF–THP, 7MeW– dK(Ac)–X9–AEF–2Nal–THP, A–A–X9–A–A–THP, A–A–X9–AEF–2Nal–THP, or d7MeW– dK(Ac)–dA–dY–d2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–A–Pen–A–2Nal–THP, 7MeW– A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal– THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW– dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, A–A–Pen–A–A–THP, A–A–Pen–AEF–2Nal–THP, or d7MeW–dK(Ac)–dA–dY–d2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen– AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W– K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal– THP, 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW– A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal– THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW– dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A– THP, 7MeW–K(Ac)–Pen–AEF–2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)– Pen–AEF–b3hF–THP, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal– THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal– THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, A–A–Pen–A–A–THP, A–A–Pen–AEF–2Nal– THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen– AEF–b3hF–THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F– K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–2Nal–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, or7MeW–K(Ac)–Pen–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW– dK(Ac)–aMeC–AEF–2Nal–THP, or d7MeW–dK(Ac)–dA–dY–d2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–X9–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X9–AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X9–AEF– 2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X9–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)– X9–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–X9–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–X9–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–X9–AEF–2Nal–THP, 7MeW–A–X9–AEF–2Nal–THP, 7MeW– b3hK–X9–AEF–2Nal–THP, 7MeW–b3hQ–X9–AEF–2Nal–THP, 7MeW–b3hQ–X9–AEF–b3hF– THP, 7MeW–dK(Ac)–X9–AEF–2Nal–THP, 7MeW–K(Ac)–X9–AEF–2Nal–A, 7MeW–K(Ac)– X9–AEF–2Nal–Aib, 7MeW–K(Ac)–X9–AEF–b3hF–THP, A–A–X9–AEF–2Nal–THP, A– K(Ac)–X9–AEF–A–THP, b3hW–K(Ac)–X9–AEF–2Nal–THP, b3hW–K(Ac)–X9–AEF–b3hF– THP, F–K(Ac)–X9–AEF–2Nal–THP, F–K(Ac)–X9–AEF–F–THP, L–K(Ac)–X9–AEF–2Nal– THP, L–K(Ac)–X9–AEF–L–THP, 7MeW–K(Ac)–X9–AEF–F–THP, or 7MeW–K(Ac)–X9– AEF–L–THP. In some embodiments, 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF– 2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF– 2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC– AEF–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)– Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF– 2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen– AEF–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW–dK(Ac)– aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF– 2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, A–A– Pen–AEF–2Nal–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F–K(Ac)–Pen–AEF–F– THP, L–K(Ac)–Pen–AEF–2Nal–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen–AEF– F–THP, or 7MeW–K(Ac)–Pen–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3NAcPh)W–K(Ac)–X9–AEF(G)– 2Nal–THP, 7MeW–A–X9–A–2Nal–THP, 7MeW–A–X9–AEF(G)–2Nal–THP, 7MeW–K(Ac)– X9–A–2Nal–THP, 7MeW–K(Ac)–X9–A–A–THP, 7MeW–K(Ac)–X9–APF–2Nal–THP, 7MeW– K(Ac)–X9–b3hY–2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–X9– F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–X9–YCF2H–2Nal–THP, A–A–X9–A–A–THP, b3hW– K(Ac)–X9–b3hY–2Nal–THP, or d7MeW–dK(Ac)–dA–dY–d2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3NAcPh)W–K(Ac)–Pen–AEF(G)– 2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–K(Ac)– Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW– K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, A–A–Pen–A–A– THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, or d7MeW–dK(Ac)–dA–dY–d2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–X9–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X9–AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF(G)– 2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X9–AEF– 2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W – K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–X9–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–X9–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–X9–AEF–2Nal– THP, 7MeW–A–X9–A–2Nal–THP, 7MeW–A–X9–AEF(G)–2Nal–THP, 7MeW–A–X9–AEF– 2Nal–THP, 7MeW–b3hK–X9–AEF–2Nal–THP, 7MeW–b3hQ–X9–AEF–2Nal–THP, 7MeW– dK(Ac)–X9–AEF–2Nal–THP, 7MeW–K(Ac)–X9–A–2Nal–THP, 7MeW–K(Ac)–X9–AEF– 2Nal–A, 7MeW–K(Ac)–X9–AEF–2Nal–Aib, 7MeW–K(Ac)–X9–APF–2Nal–THP, 7MeW– K(Ac)–X9–b3hY–2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–X9– F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–X9–YCF2H–2Nal–THP, A–A–X9–AEF–2Nal–THP, b3hW–K(Ac)–X9–AEF–2Nal–THP, b3hW–K(Ac)–X9–b3hY–2Nal–THP, d7MeW–dK(Ac)– dA–dY–d2Nal–THP, F–K(Ac)–X9–AEF–2Nal–THP, or L–K(Ac)–X9–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen– AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W– K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF– 2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen– AEF–2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW– A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal– THP, 7MeW–dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, 7MeW– K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal– Aib, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW– K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW– K(Ac)–Pen–YCF2H–2Nal–THP, A–A–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–2Nal– THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, or L–K(Ac)–Pen– AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–b3hQ–X9–AEF–b3hF–THP, 7MeW–K(Ac)–X9–A–A–THP, 7MeW–K(Ac)–X9–AEF–b3hF–THP, A–A–X9–A–A–THP, A– K(Ac)–X9–AEF–A–THP, b3hW–K(Ac)–X9–AEF–b3hF–THP, d7MeW–dK(Ac)–dA–dY– d2Nal–THP, F–K(Ac)–X9–AEF–F–THP, L–K(Ac)–X9–AEF–L–THP, 7MeW–K(Ac)–X9–AEF– F–THP, or 7MeW–K(Ac)–X9–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, A–A–Pen–A–A–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, d7MeW–dK(Ac)–dA–dY– d2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen– AEF–F–THP, or 7MeW–K(Ac)–Pen–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–X9–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X9–AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF(G)– 2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X9–AEF– 2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W – K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–X9–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–X9–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–X9–AEF–2Nal– THP, 7MeW–A–X9–A–2Nal–THP, 7MeW–A–X9–AEF(G)–2Nal–THP, 7MeW–A–X9–AEF– 2Nal–THP, 7MeW–b3hK–X9–AEF–2Nal–THP, 7MeW–b3hQ–X9–AEF–2Nal–THP, 7MeW– b3hQ–X9–AEF–b3hF–THP, 7MeW–dK(Ac)–X9–AEF–2Nal–THP, 7MeW–K(Ac)–X9–A–2Nal– THP, 7MeW–K(Ac)–X9–A–A–THP, 7MeW–K(Ac)–X9–AEF–b3hF–THP, 7MeW–K(Ac)–X9– APF–2Nal–THP, 7MeW–K(Ac)–X9–b3hY–2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlAme2)– 2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–X9–YCF2H–2Nal–THP, A–A–X9–A–A–THP, A–A–X9–AEF–2Nal–THP, A–K(Ac)–X9–AEF–A–THP, b3hW–K(Ac)– X9–AEF–2Nal–THP, b3hW–K(Ac)–X9–AEF–b3hF–THP, b3hW–K(Ac)–X9–b3hY–2Nal–THP, d7MeW–dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–X9–AEF–2Nal–THP, F–K(Ac)–X9–AEF–F– THP, L–K(Ac)–X9–AEF–2Nal–THP, L–K(Ac)–X9–AEF–L–THP, 7MeW–K(Ac)–X9–AEF–F– THP, or 7MeW–K(Ac)–X9–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF– 2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen– AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W– K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF– 2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen– AEF–2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW– A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal– THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW–dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW– dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A– THP, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW– K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)– Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, A–A–Pen–A–A–THP, A–A–Pen–AEF–2Nal–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–2Nal– THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, d7MeW– dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L– K(Ac)–Pen–AEF–2Nal–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, or 7MeW–K(Ac)–Pen–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–A or 7MeW–K(Ac)–X9–AEF–2Nal–Aib. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–A or 7MeW–K(Ac)–Pen–AEF–2Nal–Aib. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3(1NMepip)pyraz)W–K(Ac)–X9–AEF–2Nal– THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3(6AzaInd1Me))W–K(Ac)–X9–AEF– 2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3NAcPh)W–K(Ac)–X9–AEF– 2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3NAcPh)W–K(Ac)–X9–AEF(G)– 2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3NPyrazPh)W–K(Ac)–X9–AEF– 2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3NpyrlonePh)W–K(Ac)–X9– AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(5(2(4OMePh)Pyr))W– K(Ac)–X9–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(6(2OxdeQuin8Me))W –K(Ac)–X9–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10- X11-X12 is 7(6(2OxIquin))W –K(Ac)–X9–AEF–2Nal–THP. In some embodiments, X7-X8-X9- X10-X11-X12 is 7(7(124TAZP))W–K(Ac)–X9–AEF–2Nal–THP. In some embodiments, X7-X8- X9-X10-X11-X12 is 7(7(2OMeQuin))W–K(Ac)–X9–AEF–2Nal–THP. In some embodiments, X7- X8-X9-X10-X11-X12 is 7MeW–A–X9–A–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11- X12 is 7MeW–A–X9–AEF(G)–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–A–X9–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–b3hK– X9–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–b3hQ–X9–AEF– 2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–b3hQ–X9–AEF–b3hF– THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–dK(Ac)–X9–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–A–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–A–A–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–A. In some embodiments, X7-X8-X9- X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–2Nal–Aib. In some embodiments, X7-X8-X9-X10-X11- X12 is 7MeW–K(Ac)–X9–AEF–b3hF–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–APF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW– K(Ac)–X9–b3hY–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)– X9–F(4TzlAme2)–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)– X9–F(4TzlG2)–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9– YCF2H–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is A–A–X9–A–A–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is A–A–X9–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is A–K(Ac)–X9–AEF–A–THP. In some embodiments, X7-X8-X9-X10- X11-X12 is b3hW–K(Ac)–X9–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is b3hW–K(Ac)–X9–AEF–b3hF–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is b3hW– K(Ac)–X9–b3hY–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is d7MeW– dK(Ac)–dA–dY–d2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is F–K(Ac)–X9– AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is F–K(Ac)–X9–AEF–F–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is L–K(Ac)–X9–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is L–K(Ac)–X9–AEF–L–THP. In some embodiments, X7- X8-X9-X10-X11-X12 is 7MeW–K(Ac)–X9–AEF–F–THP. In some embodiments, X7-X8-X9-X10- X11-X12 is 7MeW–K(Ac)–X9–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–C–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal– THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal– THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3NAcPh)W–K(Ac)–Pen–AEF(G)– 2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3NPyrazPh)W–K(Ac)–Pen– AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(3NpyrlonePh)W–K(Ac)– Pen–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(5(2(4OMePh)Pyr))W– K(Ac)–Pen–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10- X11-X12 is 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP. In some embodiments, X7-X8-X9- X10-X11-X12 is 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP. In some embodiments, X7-X8- X9-X10-X11-X12 is 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP. In some embodiments, X7- X8-X9-X10-X11-X12 is 7MeW–A–Pen–A–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11- X12 is 7MeW–A–Pen–AEF(G)–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–A–Pen–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW– b3hK–Pen–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–b3hQ– Pen–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–b3hQ–Pen– AEF–b3hF–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–dK(Ac)–aMeC– AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–dK(Ac)–Pen–AEF– 2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–A–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–A–A–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–A. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–Aib. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–b3hF–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–APF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–b3hY–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is A–A–Pen–A–A–THP. In some embodiments, X7-X8-X9- X10-X11-X12 is A–A–Pen–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is A– K(Ac)–Pen–AEF–A–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is b3hW–K(Ac)–Pen– AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is b3hW–K(Ac)–Pen–AEF– b3hF–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is b3hW–K(Ac)–Pen–b3hY–2Nal– THP. In some embodiments, X7-X8-X9-X10-X11-X12 is d7MeW–dK(Ac)–dA–dY–d2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is F–K(Ac)–Pen–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is F–K(Ac)–Pen–AEF–F–THP. In some embodiments, X7- X8-X9-X10-X11-X12 is L–K(Ac)–Pen–AEF–2Nal–THP. In some embodiments, X7-X8-X9-X10- X11-X12 is L–K(Ac)–Pen–AEF–L–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–F–THP. In some embodiments, X7-X8-X9-X10-X11-X12 is 7MeW– K(Ac)–Pen–AEF–L–THP. In some embodiments, X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar, A–N–3Pya–Sar, b3hE– N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya– Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N– L–Sar, K(Ac)–N–5MePyridinAla–Sar, or R–N–3Pya–Sar. In some embodiments, X13-X14-X15-X16 is A–N–3Pya–Sar, b3hE–N–3Pya–Sar, dE–dN– 3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N–L–Sar, K(Ac)–N– 5MePyridinAla–Sar, or R–N–3Pya–Sar. In some embodiments, X13-X14-X15-X16 is E–N–3Pya–Sar, K(Ac)–N–3Pya–Sar, A–N– 3Pya–Sar, b3hE–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–F–3Pya– Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N–L–Sar, K(Ac)–N–5MePyridinAla– Sar, or R–N–3Pya–Sar. In some embodiments, X13-X14-X15-X16 is E–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK– bMeDTyr, or E–N–L–Sar. In some embodiments, X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar, A–N–3Pya–Sar, b3hE– N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, K(Ac)–N–5MePyridinAla–Sar, or R–N–3Pya–Sar. In some embodiments, X13-X14-X15-X16 is E–N–3Pya–Sar, K(Ac)–N–3Pya–Sar, A–N– 3Pya–Sar, b3hE–N–3Pya–Sar, dE–N–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK– bMeDTyr, E–N–L–Sar, K(Ac)–N–5MePyridinAla–Sar, or R–N–3Pya–Sar. In some embodiments, X13-X14-X15-X16 is dE–dN–3Pya–Sar, E–A–3Pya–Sar, E–A–A– Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, or E–F–3Pya–Sar. In some embodiments, X13-X14-X15-X16 is E–N–3Pya–Sar, K(Ac)–N–3Pya–Sar, A–N– 3Pya–Sar, b3hE–N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–b3hN– 3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, or R–N–3Pya–Sar. In some embodiments, X13-X14-X15-X16 is E–A–A–Sar, E–N–A–Sar, E–N–b3hF–Sar, E– N–dK–bMeDTyr, E–N–L–Sar, or K(Ac)–N–5MePyridinAla–Sar. In some embodiments, the Abu, C, or Pen in X3-X4-X5-X6 is linked to aMeC, C, or Pen in X7-X8-X9-X10-X11-X12 via a disulfide or thioether bond. In some embodiments, the Abu, C, or Pen in X3-X4-X5-X6 is linked to aMeC, C, or Pen in X7-X8-X9-X10-X11-X12 via a linkage selected from the following: In some embodiments, the Abu, C, or Pen in X3-X4-X5-X6 is linked to aMeC, C, or Pen in X7-X8-X9-X10-X11-X12 via a linkage selected from the following: The present disclosure further provides a peptide having an amino acid sequence according to any one of SEQ ID NOS: 1-89, as shown in Table 2, or a pharmaceutically acceptable salt thereof. Table 2. Example Peptides
In the peptide sequences shown above, where a number in parenthesis follows a particular residue, that residue is linked to another residue in the sequence that is denoted with the same number. For example, in the sequence MeCO-Pen(3)-N-T-7(6(2OxIquin))W-K(Ac)- Pen(3)-AEF-2Nal-THP-E-N-3Pya-Sar-CONH2 (SEQ ID NO: 88), the two Pen(3) residues are linked to one another. In another aspect, the present disclosure provides a peptide of Formula (II), comprising the amino acid sequence: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (II), or a pharmaceutically acceptable salt thereof, wherein: R1 is an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker, or R1 is AEEP or MeCO; X3 is K or R, or absent, wherein the K is conjugated to a reactive handle, optionally via a linker; X4 is an amino acid that is optionally linked to the amino acid at X9 X5 is N or Q; X6 is 7MeW or T; X7 is 7MeW, T, or W; X8 is K(Ac) or Q; X9 is an amino acid that is optionally linked to the amino acid at X4; X10 is 2Nal or AEF; X11 is AEF or 2Nal; X12 is aMeK, K, N, or THP, wherein the K is conjugated to a reactive handle, optionally via a linker; X13 is E, K, or K(Ac), wherein the K is conjugated to an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker; X14 is L, 3Pya, or N; X15 is aMeK, 3Pya, L, or THP; X16 is K, Sar, or absent, wherein the K is conjugated to a second peptide, optionally via a linker; R2 is CONH2; wherein if R1 is biotin optionally bound to the rest of the peptide via a linker, then X13 is E or X15 is L; wherein the peptide has one linkage selected from the group consisting of: a linkage between AEEP at R1 and E at X13; a linkage between X4 and X9; provided that: (i) the peptide comprises at least one moiety selected from the group consisting of an albumin-binding moiety, biotin, an imaging agent, a second peptide, and a reactive handle; or (ii) the peptide has a linkage between AEEP at R1 and E at X13; or (iii) the peptide has a linkage between X4 and X9 provided that if X4 is Abu, aMeC, C, or Pen, then X9 is not aMeC, C, or Pen. In some embodiments, the peptide has a linkage between X4 and X9, wherein the linkage is not any one of:
In some embodiments, the peptide comprises a linker between the α-carbon of X4 and the α-carbon of X9. In some embodiments, the linker is less than 24 Angstroms (Å) in length. In some embodiments, the linker is less than 20 Å in length. In some embodiments, the linker is between 4 Å and 24 Å in length. In some embodiments, the linker is between 4 Å and 20 Å in length. In some embodiments, the linker is between 10 Å and 24 Å in length. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 18 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 2 and 16 carbon atoms. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 16 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, S, and H atoms, and comprises between 4 and 16 atoms selected from C and S. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 2 and 14 carbon atoms. In some embodiments, the linker consists of C, S, and H atoms, and comprises between 2 and 14 carbon atoms. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 14 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 4 and 12 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, N, S, O, and H atoms, and comprises between 2 and 12 carbon atoms. In some embodiments, the present disclosure provides a peptide of Formula (II), comprising the amino acid sequence: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (II), or a pharmaceutically acceptable salt thereof, wherein: R1 is an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker, or R1 is AEEP or MeCO; X3 is K or R, or absent, wherein the K is conjugated to a reactive handle, optionally via a linker; X4 is 4AminoPro, A, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra X5 is N or Q; X6 is 7MeW or T; X7 is 7MeW, T, or W; X8 is K(Ac) or Q; X9 is A, aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X10 is 2Nal or AEF; X11 is AEF or 2Nal; X12 is aMeK, K, N, or THP, wherein the K is conjugated to a reactive handle, optionally via a linker; X13 is E, K, or K(Ac), wherein the K is conjugated to an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker; X14 is L, 3Pya, or N; X15 is aMeK, 3Pya, L, or THP; X16 is K, Sar, or absent, wherein the K is conjugated to a second peptide, optionally via a linker; R2 is CONH2; wherein if R1 is biotin optionally bound to the rest of the peptide via a linker, then X13 is E or X15 is L; wherein the peptide has one linkage selected from the group consisting of: a linkage between AEEP at R1 and E at X13; a linkage between 4AminoPro at X4 and D, E, or hE at X9; a linkage between Abu at X4 and aMeC, C, or Pen at X9; a linkage between aG at X4 and aG at X9; a linkage between aMeC at X4 and aMeC, C, or Pen at X9; a linkage between C at X4 and aMeC, C, or Pen at X9; a linkage between Dap at R4 and D at R9; a linkage between Pen at R4 and aMeC, C, or Pen at R9; a linkage between Pen(oXyl) at R4 and Pen at R9; a linkage between Pen(mXyl) at R4 and Pen at R9; a linkage between Pen(pXyl) at R4 and Pen at R9; and a linkage between Pra at R4 and Dap(N3) at X9; provided that: (i) the peptide comprises at least one moiety selected from the group consisting of an albumin-binding moiety, biotin, an imaging agent, a second peptide, and a reactive handle; or (ii) the peptide has a linkage between AEEP at R1 and E at X13, between 4AminoPro at X4 and D at X9, between 4AminoPro at X4 and E at X9, between 4AminoPro at X4 and hE at X9, between aG at X4 and aG at X9, between Dap at R4 and D at R9, between Pen(mXyl) at R4 and Pen at R9, between Pen(mXyl) at R4 and Pen at R9, between Pen(pXyl) at R4 and Pen at R9, or between Pra at R4 and Dap(N3) at X9. In some embodiments, the present disclosure provides a peptide of Formula (II), comprising the amino acid sequence: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (II), or a pharmaceutically acceptable salt thereof, wherein: R1 is an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker, or R1 is AEEP or MeCO; X3 is dK or dR, or absent, wherein the dK is conjugated to a reactive handle, optionally via a linker; X4 is 4AminoPro, A, Abu, Dap, Pen, or Pra X5 is N or Q; X6 is 7MeW or T; X7 is 7MeW, T, or W; X8 is K(Ac) or Q; X9 is A, C, D, Dap, E, hE, or Pen; X10 is 2Nal or AEF; X11 is AEF or 2Nal; X12 is aMeK, K, N, or THP, wherein the K is conjugated to a reactive handle, optionally via a linker; X13 is E, K, or K(Ac), wherein the K is conjugated to an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker; X14 is dL, 3Pya, or N; X15 is aMeK, 3Pya, dL, or THP; X16 is K, Sar, or absent, wherein the K is conjugated to a second peptide, optionally via a linker; R2 is CONH2; wherein if R1 is biotin optionally bound to the rest of the peptide via a linker, then X13 is E or X15 is dL; wherein the peptide has one linkage selected from the group consisting of: a linkage between AEEP at R1 and E at X13; a linkage between 4AminoPro at X4 and E at X9; a linkage between 4AminoPro at X4 and hE at X9; a linkage between Abu at X4 and C at X9; a linkage between Dap at R4 and D at R9; a linkage between Pen at R4 and Pen at R9; and a linkage between Pra at R4 and Dap(N3) at X9; provided that: (i) the peptide comprises at least one moiety selected from the group consisting of an albumin-binding moiety, biotin, an imaging agent, a second peptide, and a reactive handle; or (ii) the peptide has a linkage between AEEP at R1 and E at X13, between 4AminoPro at X4 and E at X9, between 4AminoPro at X4 and hE at X9, between Dap at R4 and D at R9, or between Pra at R4 and Dap(N3) at X9. In some embodiments, the present disclosure provides a peptide of Formula (II-A), comprising the amino acid sequence: R1-X3-X4-N-T-X7-K(Ac)-X9-AEF-2Nal-X12-X13-N-X15-X16-R2 (II-A), or a pharmaceutically acceptable salt thereof, wherein: R1 is an albumin-binding moiety, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker, or R1 is AEEP or MeCO; X3 is K or R, or absent, wherein the K is conjugated to a reactive handle, optionally via a linker; X4 is 4AminoPro, A, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra X7 is 7MeW or W; X9 is A, aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X12 is aMeK, K, or THP, wherein the K is conjugated to a reactive handle, optionally via a linker; X13 is E, K, or K(Ac), wherein the K is conjugated to an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker; X15 is 3Pya or L; X16 is K, Sar, or absent, wherein the K is conjugated to a second peptide, optionally via a linker; R2 is CONH2; wherein the peptide has one linkage selected from the group consisting of: a linkage between AEEP at R1 and E at X13; a linkage between 4AminoPro at X4 and D, E, or hE at X9; a linkage between Abu at X4 and aMeC, C, or Pen at X9; a linkage between aG at X4 and aG at X9; a linkage between aMeC at X4 and aMeC, C, or Pen at X9; a linkage between C at X4 and aMeC, C, or Pen at X9; a linkage between Dap at R4 and D at R9; a linkage between Pen at R4 and aMeC, C, or Pen at R9; a linkage between Pen(oXyl) at R4 and Pen at R9; a linkage between Pen(mXyl) at R4 and Pen at R9; a linkage between Pen(pXyl) at R4 and Pen at R9; and a linkage between Pra at R4 and Dap(N3) at X9; provided that: (i) the peptide comprises at least one moiety selected from the group consisting of an albumin-binding moiety, biotin, an imaging agent, a second peptide, and a reactive handle; or (ii) the peptide has a linkage between AEEP at R1 and E at X13, between 4AminoPro at X4 and D at X9, between 4AminoPro at X4 and E at X9, between 4AminoPro at X4 and hE at X9, between aG at X4 and aG at X9, between Dap at R4 and D at R9, between Pen(mXyl) at R4 and Pen at R9, between Pen(mXyl) at R4 and Pen at R9, between Pen(pXyl) at R4 and Pen at R9, or between Pra at R4 and Dap(N3) at X9. In some embodiments, the present disclosure provides a peptide of Formula (II-A), comprising the amino acid sequence: R1-X3-X4-N-T-X7-K(Ac)-X9-AEF-2Nal-X12-X13-N-X15-X16-R2 (II-A), or a pharmaceutically acceptable salt thereof, wherein: R1 is an albumin-binding moiety, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker, or R1 is AEEP or MeCO; X3 is dK or dR, or absent, wherein the dK is conjugated to a reactive handle, optionally via a linker; X4 is 4AminoPro, A, Abu, Dap, Pen, or Pra X7 is 7MeW or W; X9 is A, C, D, Dap, E, hE, or Pen; X12 is aMeK, K, or THP, wherein the K is conjugated to a reactive handle, optionally via a linker; X13 is E, K, or K(Ac), wherein the K is conjugated to an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker; X15 is 3Pya or dL; X16 is K, Sar, or absent, wherein the K is conjugated to a second peptide, optionally via a linker; R2 is CONH2; wherein the peptide has one linkage selected from the group consisting of: a linkage between AEEP at R1 and E at X13; a linkage between 4AminoPro at X4 and E at X9; a linkage between 4AminoPro at X4 and hE at X9; a linkage between Abu at X4 and C at X9; a linkage between Dap at R4 and D at R9; a linkage between Pen at R4 and Pen at R9; and a linkage between Pra at R4 and Dap(N3) at X9; provided that: (i) the peptide comprises at least one moiety selected from the group consisting of an albumin-binding moiety, biotin, an imaging agent, a second peptide, and a reactive handle; or (ii) the peptide has a linkage between AEEP at R1 and E at X13, between 4AminoPro at X4 and E at X9, between 4AminoPro at X4 and hE at X9, between Dap at R4 and D at R9, or between Pra at R4 and Dap(N3) at X9. In some embodiments, the peptide contains one, and only one, linkage selected from the group consisting of: a linkage between AEEP at R1 and E at X13; a linkage between 4AminoPro at X4 and D, E, or hE at X9; a linkage between Abu at X4 and aMeC, C, or Pen at X9; a linkage between aG at X4 and aG at X9; a linkage between aMeC at X4 and aMeC, C, or Pen at X9; a linkage between C at X4 and aMeC, C, or Pen at X9; a linkage between Dap at R4 and D at R9; a linkage between Pen at R4 and aMeC, C, or Pen at R9; a linkage between Pen(oXyl) at R4 and Pen at R9; a linkage between Pen(mXyl) at R4 and Pen at R9; a linkage between Pen(pXyl) at R4 and Pen at R9; and a linkage between Pra at R4 and Dap(N3) at X9. In some embodiments, R1 is an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker. In some embodiments, R1 is an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle. In some embodiments, R1 is an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, each of which is bound to the rest of the peptide via a linker. In some embodiments, R1 is an albumin-binding moiety optionally bound to the rest of the peptide via a linker. In some embodiments, R1 is biotin optionally bound to the rest of the peptide via a linker. In some embodiments, R1 is an imaging agent optionally bound to the rest of the peptide via a linker. In some embodiments, R1 is a second peptide optionally bound to the rest of the peptide via a linker. In some embodiments, R1 is a reactive handle optionally bound to the rest of the peptide via a linker. In some embodiments, R1 is AEEP or MeCO. In some embodiments, R1 is AEEP. In some embodiments, R1 is AEEP linked to E at X13. In some embodiments, R1 is MeCO. In some embodiments, R3 is K or R, or absent, wherein the K is conjugated to a reactive handle, optionally via a linker, and wherein each of K and R are L-amino acids. In some embodiments, R3 is dK or dR, or absent, wherein the dK is conjugated to a reactive handle, optionally via a linker. In some embodiments, R3 is K conjugated to a reactive handle, optionally via a linker. In some embodiments, R3 is R. In some embodiments, R3 is absent. In some embodiments, R3 is dK conjugated to a reactive handle, optionally via a linker. In some embodiments, R3 is dR. In some embodiments, X4 is 4AminoPro, A, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra, each of which is an L amino acid. In some embodiments, X4 is 4Amino-dPro, dAbu, d-aG, aMe-dC, dC, dDap, dPen, dPen(oXyl), dPen(mXyl), dPen(pXyl), or dPra. In some embodiments, X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra. In some embodiments, X4 is 4AminoPro, A, Abu, Dap, Pen, or Pra. In some embodiments, X4 is 4AminoPro, Abu, Dap, Pen, or Pra. In some embodiments, X4 is 4AminoPro, aG, Dap, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra. In some embodiments, X4 is Abu, aMeC, C, Pen, Pen(oXyl), Pen(mXyl), or Pen(pXyl). In some embodiments, X4 is Abu, aMeC, C, or Pen. In some embodiments, X4 is Abu, C, or Pen. In some embodiments, X4 is Abu or Pen. In some embodiments, X4 is 4AminoPro. In some embodiments, X4 is 4RAminoPro. In some embodiments, X4 is 4SAminoPro. In some embodiments, X4 is A. In some embodiments, X4 is Abu. In some embodiments, X4 is aG. In some embodiments, X4 is aMeC. In some embodiments, X4 is C. In some embodiments, X4 is Dap. In some embodiments, X4 is Pen. In some embodiments, X4 is Pen(oXyl). In some embodiments, X4 is Pen(mXyl). In some embodiments, X4 is Pen(pXyl). In some embodiments, X4 is Pra. In some embodiments, X4 is 4Amino-dPro. In some embodiments, X4 is 4RAmino-dPro. In some embodiments, X4 is 4SAmino-dPro. In some embodiments, X4 is dA. In some embodiments, X4 is dAbu. In some embodiments, X4 is d-aG. In some embodiments, X4 is aMe- dC. In some embodiments, X4 is dC. In some embodiments, X4 is dDap. In some embodiments, X4 is dPen. In some embodiments, X4 is dPen(oXyl). In some embodiments, X4 is dPen(mXyl). In some embodiments, X4 is dPen(pXyl). In some embodiments, X4 is dPra. In some embodiments, X5 is N or Q, each of which is an L-amino acid. In some embodiments, X5 is dN or dQ. In some embodiments, X5 is N. In some embodiments, X5 is Q. In some embodiments, X5 is dN. In some embodiments, X5 is dQ. In some embodiments, X6 is 7MeW or T, each of which is an L-amino acid. In some embodiments, X6 is d7MeW or dT. In some embodiments, X6 is 7MeW. In some embodiments, X6 is T. In some embodiments, X6 is d7MeW. In some embodiments, X6 is dT. In some embodiments, X7 is 7MeW, T, or W, each of which is an L-amino acid. In some embodiments, X7 is d7MeW, dT, or dW. In some embodiments, X7 is 7MeW or W. In some embodiments, X7 is 7MeW. In some embodiments, X7 is T. In some embodiments, X7 is W. In some embodiments, X7 is d7MeW. In some embodiments, X7 is dT. In some embodiments, X7 is dW. In some embodiments, X8 is K(Ac) or Q, each of which is an L-amino acid. In some embodiments, X8 is dK(Ac) or dQ. In some embodiments, X8 is K(Ac). In some embodiments, X8 is Q. In some embodiments, X8 is dK(Ac). In some embodiments, X8 is dQ. In some embodiments, X9 is A, aMeC, aG, C, D, E, hE, Pen, or Dap(N3), each of which is an L-amino acid. In some embodiments, X9 is dA, aMe-dC, d-aG, dC, dD, dE, d-hE, dPen, or dDap(N3). In some embodiments, X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3). In some embodiments, X9 is A, C, D, E, hE, Pen, or Dap(N3). In some embodiments, X9 is C, D, E, hE, Pen, or Dap(N3). In some embodiments, X9 is aG, D, E, hE, or Dap(N3). In some embodiments, X9 is aMeC, C, or Pen. In some embodiments, X9 is aMeC or Pen. In some embodiments, X9 is aMeC. In some embodiments, X9 is aG. In some embodiments, X9 is C. In some embodiments, X9 is D. In some embodiments, X9 is E. In some embodiments, X9 is hE. In some embodiments, X9 is Pen. In some embodiments, X9 is Dap(N3). In some embodiments, X9 is dA. In some embodiments, X9 is aMe-dC. In some embodiments, X9 is d-aG. In some embodiments, X9 is dC. In some embodiments, X9 is dD. In some embodiments, X9 is dE. In some embodiments, X9 is d-hE. In some embodiments, X9 is dPen. In some embodiments, X9 is dDap(N3). In some embodiments, X10 is 2Nal or AEF, each of which is an L-amino acid. In some embodiments, X10 is d2Nal or dAEF. In some embodiments, X10 is 2Nal. In some embodiments, X10 is AEF. In some embodiments, X10 is d2Nal. In some embodiments, X10 is dAEF. In some embodiments, X11 is AEF or 2Nal, each of which is an L-amino acid. In some embodiments, X11 is dAEF or d2Nal. In some embodiments, X11 is AEF. In some embodiments, X11 is 2Nal. In some embodiments, X11 is dAEF. In some embodiments, X11 is d2Nal. In some embodiments, X12 is aMeK, K, N, or THP, wherein the K is conjugated to a reactive handle, optionally via a linker, and wherein the aMeK, K, and N are L-amino acids. In some embodiments, X12 is d-aMeK, dK, dN, or THP, wherein the dK is conjugated to a reactive handle, optionally via a linker. In some embodiments, X12 is aMeK, K, or THP, wherein the K is conjugated to a reactive handle, optionally via a linker. In some embodiments, X12 is aMeK. In some embodiments, X12 is K conjugated to a reactive handle, optionally via a linker. In some embodiments, X12 is N. In some embodiments, X12 is THP. In some embodiments, X12 is d- aMeK. In some embodiments, X12 is dK conjugated to a reactive handle, optionally via a linker. In some embodiments, X12 is dN. In some embodiments, X13 is E, K, or K(Ac), wherein the K is conjugated to an albumin- binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker, and wherein the E, K, and K(Ac) are L-amino acids. In some embodiments, X13 is dE, dK, or dK(Ac), wherein the dK is conjugated to an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker. In some embodiments, X13 is E. In some embodiments, X13 is K conjugated to an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker. In some embodiments, X13 is K conjugated to an albumin-binding moiety, optionally via a linker. In some embodiments, X13 is K conjugated to biotin, optionally via a linker. In some embodiments, X13 is K conjugated to an imaging agent, optionally via a linker. In some embodiments, X13 is K conjugated to a second peptide, optionally via a linker. In some embodiments, X13 is K conjugated to a reactive handle, optionally via a linker. In some embodiments, X13 is K(Ac). In some embodiments, X13 is dE. In some embodiments, X13 is dK conjugated to an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker. In some embodiments, X13 is dK conjugated to an albumin-binding moiety, optionally via a linker. In some embodiments, X13 is dK conjugated to biotin, optionally via a linker. In some embodiments, X13 is dK conjugated to an imaging agent, optionally via a linker. In some embodiments, X13 is dK conjugated to a second peptide, optionally via a linker. In some embodiments, X13 is dK conjugated to a reactive handle, optionally via a linker. In some embodiments, X13 is dK(Ac). In some embodiments, X14 is L, 3Pya, or N, each of which is an L-amino acid. In some embodiments, X14 is dL, d3Pya, or dN. In some embodiments, X14 is dL, 3Pya, or N. In some embodiments, X14 is L. In some embodiments, X14 is 3Pya. In some embodiments, X14 is N. In some embodiments, X14 is dL. In some embodiments, X14 is d3Pya. In some embodiments, X14 is dN. In some embodiments, X15 is aMeK, 3Pya, L, or THP, wherein the aMeK, 3Pya, and L are L-amino acids. In some embodiments, X15 is d-aMeK, d3Pya, dL, or THP. In some embodiments, X15 is aMeK, 3Pya, dL, or THP. In some embodiments, X15 is 3Pya or dL. In some embodiments, X15 is aMeK. In some embodiments, X15 is 3Pya. In some embodiments, X15 is L. In some embodiments, X15 is THP. In some embodiments, X15 is d-aMeK. In some embodiments, X15 is d3Pya. In some embodiments, X15 is dL. In some embodiments, X16 is K, Sar, or absent, wherein the K is conjugated to a second peptide, optionally via a linker, wherein the K is an L-amino acid. In some embodiments, X16 is dK, Sar, or absent, wherein the dK is conjugated to a second peptide, optionally via a linker. In some embodiments, X16 is K conjugated to a second peptide, optionally via a linker. In some embodiments, X16 is dK conjugated to a second peptide, optionally via a linker. In some embodiments, X16 is Sar. In some embodiments, X16 is absent. In some embodiments, X13 is E or X15 is L. In some embodiments, X13 is E or X15 is dL. In some embodiments, the peptide comprises at least one moiety selected from the group consisting of an albumin-binding moiety, biotin, an imaging agent, a second peptide, and a reactive handle. In some embodiments, the peptide comprises at least one moiety selected from the group consisting of an albumin-binding moiety, biotin, an imaging agent, a second peptide, and a reactive handle at R1 or at X13. In some embodiments, the albumin-binding moiety, biotin, imaging agent, second peptide, or reactive handle is bound to the rest of the peptide via a linker. Identification, selection, and/or synthesis of a suitable linker is within the purview of one of ordinary skill in the art. In some embodiments, the linker may be an aliphatic chain. In some embodiments, the linker may be a polyethylene glycol chain (i.e., a chain containing two or more repeating units of the following structure: -CH2CH2O-). In some embodiments, the linker comprises an adduct of a click chemistry reaction, such as a triazole resulting from an alkyne-azide cycloaddition reaction. In some embodiments, the peptide comprises an albumin-binding moiety. As used herein, the term “albumin-binding moiety” refers to a moiety, usually a small molecule or a fragment of a small molecule, that reversibly binds to albumin in the blood and thereby increases serum circulation time of the agent to which it is attached in a subject. In some embodiments, the albumin-binding moiety is diflunisal, indomethacin, 4-(p-iodophenyl)butyric acid, or an Evans blue dye fragment. In some embodiments, the albumin-binding moiety is diflunisal or 4-(p- iodophenyl)butyric acid. In some embodiments, the albumin-binding moiety is diflunisal. In some embodiments, the albumin-binding moiety is indomethacin. In some embodiments, the albumin-binding moiety is 4-(p-iodophenyl)butyric acid. In some embodiments, the albumin- binding moiety is an Evans blue dye fragment. In some embodiments, the peptide comprises biotin. In some embodiments, the peptide comprises an imaging agent. In some embodiments, the imaging agent is a fluorescent agent. In some embodiments, the imaging agent is a radioisotope. In some embodiments, the imaging agent is a dye. In some embodiments, the imaging agent is a radioisotopically labeled polyethylene glycol chain, Cy5, or fluorescein (FITC). In some embodiments, the imaging agent is a radioisotopically labeled polyethylene glycol chain. In some embodiments, the imaging agent is Cy5. In some embodiments, the imaging agent is fluorescein (FITC). In some embodiments, the peptide is conjugated to a second peptide. In some embodiments, the conjugate of the peptide and the second peptide is a homodimer (i.e., the sequence of the peptide and the sequence of the second peptide are identical). In some embodiments, the conjugate of the peptide and the second peptide is a heterodimer (i.e., the sequence of the peptide and the sequence of the second peptide are not identical). In some embodiments, the second peptide is an interleukin-23 receptor inhibitor. In some embodiments, the second peptide is not an interleukin-23 receptor inhibitor. In some embodiments, the peptide comprises a reactive handle. As used herein, the term “reactive handle” refers to a reactive chemical moiety or functional group that may be reacted with a compatible reactive group on a second molecule to form an adduct. In some embodiments, the reactive handle is a reactive partner in a click chemistry reaction (e.g., a bioorthogonal click chemistry reaction), such as an alkyne-azide cycloaddition. Accordingly, in some embodiments, the reactive handle is an alkyne. In some embodiments, the reactive handle is pentynoic acid. In some embodiments, the reactive handle is an azide. In other embodiments, the reactive handle is an α-halo carbonyl. In some embodiments, the α-halo carbonyl is an α-iodo carbonyl, an α-bromo carbonyl, or an α-chloro carbonyl. In some embodiments, the peptide has a linkage between AEEP at R1 and E at X13, between 4AminoPro at X4 and D at X9, between 4AminoPro at X4 and E at X9, between 4AminoPro at X4 and hE at X9, between aG at X4 and aG at X9, between Dap at R4 and D at R9, between Pen(mXyl) at R4 and Pen at R9, between Pen(mXyl) at R4 and Pen at R9, between Pen(pXyl) at R4 and Pen at R9, or between Pra at R4 and Dap(N3) at X9. In some embodiments, the peptide has a linkage between AEEP at R1 and E at X13, between 4AminoPro at X4 and E at X9, between 4AminoPro at X4 and hE at X9, between Dap at R4 and D at R9, or between Pra at R4 and Dap(N3) at X9. In some embodiments, the peptide has an amide linkage between AEEP R1 and E at X13. In some embodiments, the peptide has an amide linkage between 4AminoPro at X4 and D at X9. In some embodiments, the peptide has an amide linkage between 4AminoPro at X4 and E at X9. In some embodiments, the peptide has an amide linkage between 4AminoPro at X4 and hE at X9. In some embodiments, the peptide has an aliphatic linkage between aG at X4 and aG at X9. In some embodiments, the peptide has an amide linkage between Dap at R4 and D at R9. In some embodiments, the peptide has a thioether linkage between Pen(mXyl) at R4 and Pen at R9 In some embodiments, the peptide has a thioether linkage between Pen(mXyl) at R4 and Pen at R9 In some embodiments, the peptide has a thioether linkage between Pen(pXyl) at R4 and Pen at R9 In some embodiments, the peptide has a triazolyl linkage between Pra at R4 and Dap(N3) at X9. In some embodiments, the peptide comprises a linkage between R1 and X13 having a structure selected from the following: AEEP – E. In some embodiments, the peptide is cyclized via a linkage between the residues at X4 and X9 having a structure selected from the following: In some embodiments, the peptide is cyclized via a linkage between the residues at X4 and X9 having a structure selected from the following: The present disclosure further provides a peptide having an amino acid sequence according to any one of SEQ ID NOS: 90-136, as shown in Table 3, or a pharmaceutically acceptable salt thereof. Table 3. Example Peptides
In the peptide sequences shown above, where a number in parenthesis follows a particular residue, that residue is linked to another residue in the sequence that is denoted with the same number. For example, in the sequence MeCO-Pen(3)-N-T-7MeW-K(Ac)-Pen(3)-AEF- 2Nal-THP-K(dPEG12AcBr)-N-3Pya-Sar-CONH2 (SEQ ID NO: 130), the two Pen(3) residues are linked to one another. In another aspect, the present disclosure provides a peptide of Formula (III), comprising the amino acid sequence: R1-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III), or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, MeCO, or PyE; X6 is 3OHPro, Aib, T, or absent; X7 is 7MeW or absent; X8 is Aib, K(Ac), K(NMeAc), R5Me, S5Me, or absent; X9 is Aib, aMePra, hC(pXyl), K, Pen, R5H, S5H, R5Me, S5Me, or absent; X10 is 4OMeF, AEF, F, hK, R5H, S5H, or absent; X11 is 2Nal or 6OH2Nal; X12 is aMeK, R5Me, S5Me, or THP; X13 is aMeK(N3), E, hC, hE, K(Ac), Q, R5H, S5H, R5Me, or S5Me; X14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(iBu)Gly, Sar, or absent; and R2 is CONH2 or CONH(PEG3a); wherein: when X10 is absent, X6, X7, X8, and X9 are also absent, when X9 is absent, X6, X7, and X8 are also absent, when X8 is absent, X6 and X7 are also absent, and when X7 is absent X6 is also absent; and wherein the peptide optionally contains one linkage selected from the group consisting of a linkage between R1 and X13, a linkage between R1 and X14, a linkage between X8 and X12, a linkage between X9 and X13, a linkage between X10 and X13, and a linkage between X10 and X14. In some embodiments, the present disclosure provides a peptide of Formula (III), comprising the amino acid sequence: R1-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III), or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, MeCO, or PyE; X6 is 3OHPro, Aib, T, or absent; X7 is 7MeW or absent; X8 is Aib, K(Ac), K(NMeAc), R5Me, S5Me, or absent; X9 is Aib, aMePra, hC(pXyl), K, Pen, R5H, S5H, R5Me, S5Me, or absent; X10 is 4OMeF, AEF, F, hK, R5H, S5H, or absent; X11 is 2Nal or 6OH2Nal; X12 is aMeK, R5Me, S5Me, or THP; X13 is aMeK(N3), E, hC, hE, K(Ac), Q, R5H, S5H, R5Me, or S5Me; X14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(iBu)Gly, Sar, or absent; and R2 is CONH2 or CONH(PEG3a); wherein: when X10 is absent, X6, X7, X8, and X9 are also absent, when X9 is absent, X6, X7, and X8 are also absent, when X8 is absent, X6 and X7 are also absent, and when X7 is absent X6 is also absent; wherein: when R1 is 5Ava, the 5Ava is linked to an E at X13 or an hE at X13; when R1 is 6Ahx, the 6Ahx is optionally linked to an E at X13 or an hE at X13; when R1 is 7Ahp, the 7Ahp is linked to an E at X13 or an hE at X13 or a D at X14; when R1 is 8Aoc, the 8Aoc is linked to an E at X13 an hE at X13; when R1 is bAla, the bAla is linked to an E at X13 or an hE at X13; when X8 is R5Me, the R5Me is linked to an R5Me or an S5Me at X12; when X8 is S5Me, the S5Me is linked to an R5Me or an S5Me at X12; when X9 is aMePra, the aMePra is linked to an aMeK(N3) at X13; when X9 is hC(pXyl), the hC(pXyl) is linked to an hC at X13; when X9 is K, the K is optionally linked to an E at X13 or an hE at X13; when X9 is R5H, the R5H is optionally linked to an R5H at X13, an S5H at X13, an R5Me at X13, or an S5Me at X13; when X9 is S5H, the S5H is optionally linked to an R5H at X13, an S5H at X13, an R5Me at X13, or an S5Me at X13; when X9 is R5Me, the R5Me is optionally linked to an R5H at X13, an S5H at X13, an R5Me at X13,or an S5Me at X13; when X9 is S5Me, the S5Me is optionally linked to an R5H at X13, an S5H at X13, an R5Me at X13,or an S5Me at X13; when X10 is AEF, the AEF is optionally linked to an E at X13 or an hE at X14; when X10 is hK, the hK is linked to a D at X14; when X10 is R5H, the R5H is linked to an R5H at X14 or an S5H at X14; when X10 is S5H, the S5H is linked to an R5H at X14 or an S5H at X14; when X12 is R5Me, the R5Me is linked to an R5Me at X8 or an S5Me at X8; when X12 is S5Me, the S5Me is linked to an R5Me at X8 or an S5Me at X8; when X13 is aMeK(N3), the aMeK(N3) is linked to an aMePra at X9; when X13 is E, the E is optionally linked to a 5Ava at R1, a 6Ahx at R1, a 7Ahp at R1, an 8Aoc at R1, a bAla at R1, a K at X9, or an AEF at X10; when X13 is hC, the hC is linked to an hC(pXyl) at X9; when X13 is hE, the hE is linked to a 5Ava at R1, a 6Ahx at R1, a 7Ahp at R1, an 8Aoc at R1, or a bAla at R1; when X13 is R5H, the R5H is optionally linked to an S5H at X9, an S5H at X9, an R5Me at X9, or an S5Me at X9; when X13 is S5H, the S5H is optionally linked to an S5H at X9, an S5H at X9, an R5Me at X9, or an S5Me at X9; when X13 is S5Me, the S5Me is optionally linked to an S5H at X9, an S5H at X9, an R5Me at X9, or an S5Me at X9; when X14 is D, the D is linked to a 7Ahp at R1 or an hK at X10; when X14 is hE, the hE is linked to an AEF at X10; when X14 is R5H, the R5H is linked to an R5H at X10 or an S5H at X10; and when X14 is S5H, the S5H is linked to an R5H at X10 or an S5H at X10; wherein: the peptide contains no more than one linkage selected from the group consisting of a linkage between R1 and X13, a linkage between R1 and X14, a linkage between X8 and X12, a linkage between X9 and X13, a linkage between X10 and X13, and a linkage between X10 and X14. In some embodiments, disclosed herein is a peptide of Formula (III), comprising the amino acid sequence: R1-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III), or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, MeCO, or PyE; X6 is 3OHPro, Aib, T, or absent; X7 is 7MeW or absent; X8 is Aib, K(Ac), K(NMeAc), R5Me, S5Me, or absent; X9 is Aib, aMePra, hC(pXyl), K, Pen, R5H, S5H, R5Me, S5Me, or absent; X10 is 4OMeF, AEF, F, hK, R5H, S5H, or absent; X11 is 2Nal or 6OH2Nal; X12 is aMeK, R5Me, S5Me, or THP; X13 is aMeK(N3), E, hC, hE, K(Ac), Q, R5H, S5H, R5Me, or S5Me; X14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(iBu)Gly, Sar, or absent; and R2 is CONH2 or CONH(PEG3a); wherein: when X10 is absent, X6, X7, X8, and X9 are also absent, when X9 is absent, X6, X7, and X8 are also absent, when X8 is absent, X6 and X7 are also absent, and when X7 is absent X6 is also absent; wherein: when R1 is 5Ava, the 5Ava is linked to an E at X13 or an hE at X13; when R1 is 6Ahx, the 6Ahx is optionally linked to an E at X13 or an hE at X13; when R1 is 7Ahp, the 7Ahp is linked to an E at X13 or an hE at X13 or a D at X14; when R1 is 8Aoc, the 8Aoc is linked to an E at X13 an hE at X13; when R1 is bAla, the bAla is linked to an E at X13 or an hE at X13; when X8 is R5Me, the R5Me is linked to an R5Me or an S5Me at X12; when X8 is S5Me, the S5Me is linked to an R5Me or an S5Me at X12; when X9 is aMePra, the aMePra is linked to an aMeK(N3) at X13; when X9 is hC(pXyl), the hC(pXyl) is linked to an hC at X13; when X9 is K, the K is optionally linked to an E at X13 or an hE at X13; when X9 is R5H, the R5H is optionally linked to an R5H at X13, an S5H at X13, an R5Me at X13, or an S5Me at X13; when X9 is S5H, the S5H is optionally linked to an R5H at X13, an S5H at X13, an R5Me at X13, or an S5Me at X13; when X9 is R5Me, the R5Me is optionally linked to an R5H at X13, an S5H at X13, an R5Me at X13,or an S5Me at X13; when X9 is S5Me, the S5Me is optionally linked to an R5H at X13, an S5H at X13, an R5Me at X13,or an S5Me at X13; when X10 is AEF, the AEF is optionally linked to an E at X13 or an hE at X14; when X10 is hK, the hK is linked to a D at X14; when X10 is R5H, the R5H is linked to an R5H at X14 or an S5H at X14; when X10 is S5H, the S5H is linked to an R5H at X14 or an S5H at X14; when X12 is R5Me, the R5Me is linked to an R5Me at X8 or an S5Me at X8; when X12 is S5Me, the S5Me is linked to an R5Me at X8 or an S5Me at X8; when X13 is aMeK(N3), the aMeK(N3) is linked to an aMePra at X9; when X13 is E, the E is optionally linked to a 5Ava at R1, a 6Ahx at R1, a 7Ahp at R1, an 8Aoc at R1, a bAla at R1, a K at X9, or an AEF at X10; when X13 is hC, the hC is linked to an hC(pXyl) at X9; when X13 is hE, the hE is linked to a 5Ava at R1, a 6Ahx at R1, a 7Ahp at R1, an 8Aoc at R1, or a bAla at R1; when X13 is R5H, the R5H is optionally linked to an S5H at X9, an S5H at X9, an R5Me at X9, or an S5Me at X9; when X13 is S5H, the S5H is optionally linked to an S5H at X9, an S5H at X9, an R5Me at X9, or an S5Me at X9; when X13 is S5Me, the S5Me is optionally linked to an S5H at X9, an S5H at X9, an R5Me at X9, or an S5Me at X9; when X14 is D, the D is linked to a 7Ahp at R1 or an hK at X10; when X14 is hE, the hE is linked to an AEF at X10; when X14 is R5H, the R5H is linked to an R5H at X10 or an S5H at X10; and when X14 is S5H, the S5H is linked to an R5H at X10 or an S5H at X10; wherein: the peptide contains no more than one linkage selected from the group consisting of a linkage between R1 and X13, a linkage between R1 and X14, a linkage between X8 and X12, a linkage between X9 and X13, a linkage between X10 and X13, and a linkage between X10 and X14. In some embodiments, R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO. In some embodiments, R1 is 5Ava, 6Ahx, 7Ahp, or 8Aoc. In some embodiments, R1 is 5Ava. In some embodiments, R1 is 6Ahx. In some embodiments, R1 is 7Ahp. In some embodiments, R1 is 8Aoc. In some embodiments, R1 is bAla. In some embodiments, R1 is MeCO. In some embodiments, R1 is PyE. In some embodiments, X6 is 3OHPro, Aib, T, or absent, wherein the 3OHPro and the T are L-amino acids. In some embodiments, X6 is d-3OHPro, Aib, dT, or absent. In some embodiments, X6 is 3OHPro. In some embodiments, X6 is d-3OHPro. In some embodiments, X6 is Aib. In some embodiments, X6 is T. In some embodiments, X6 is dT. In some embodiments, X6 is absent. In some embodiments, X7 is 7MeW. In some embodiments, X7 is 7MeW, wherein the 7MeW is an L-amino acid. In some embodiments, X7 is d7MeW. In some embodiments, X7 is absent. In some embodiments, X8 is Aib, K(Ac), K(NMeAc), R5Me, S5Me, or absent, wherein the K(Ac) and K(NMeAc) are L-amino acids. In some embodiments, X8 is Aib, dK(Ac) dK(NMeAc), R5Me, S5Me, or absent. In some embodiments, X8 is Aib, K(Ac), or absent. In some embodiments, X8 is R5Me or S5Me. In some embodiments, X8 is Aib. In some embodiments, X8 is K(Ac). In some embodiments, X8 is dK(Ac). In some embodiments, X8 is K(NMeAc). In some embodiments, X8 is dK(NMeAc). In some embodiments, X8 is R5Me. In some embodiments, X8 is S5Me. In some embodiments, X8 is absent. In some embodiments, X9 is Aib, aMePra, hC(pXyl), K, Pen, R5H, S5H, R5Me, S5Me, or absent, wherein the aMePra, hC(pXyl), K, and Pen are L-amino acids. In some embodiments, X9 is Aib, d-aMePra, d-hC(pXyl), dK, dPen, R5H, S5H, R5Me, S5Me, or absent. In some embodiments, X9 is aMePra, hC(pXyl), K, RS5, S5H, R5Me, S5Me, or absent. In some embodiments, X9 is K, R5H, S5H, S5Me, S5Me, or absent. In some embodiments, X9 is Aib. In some embodiments, X9 is aMePra. In some embodiments, X9 is d-aMePra. In some embodiments, X9 is hC(pXyl). In some embodiments, X9 is d-hC(pXyl). In some embodiments, X9 is K. In some embodiments, X9 is dK. In some embodiments, X9 is Pen. In some embodiments, X9 is dPen. In some embodiments, X9 is R5H. In some embodiments, X9 is S5H. In some embodiments, X9 is R5Me. In some embodiments, X9 is S5Me. In some embodiments, X9 is absent. In some embodiments, X10 is 4OMeF, AEF, F, hK, R5H, S5H, or absent, wherein the 4OMeF, AEF, F, and hK are L-amino acids. In some embodiments, X10 is d4OMeF, dAEF, dF, d-hK, R5H, S5H, or absent. In some embodiments, X10 is 4OMeF, AEF, F, hK, R5Me, S5H, or absent. In some embodiments, X10 is AEF, hK, R5H, S5H, or absent. In some embodiments, X10 is 4OMeF. In some embodiments, X10 is d4OMeF. In some embodiments, X10 is AEF. In some embodiments, X10 is dAEF. In some embodiments, X10 is F. In some embodiments, X10 is dF. In some embodiments, X10 is hK. In some embodiments, X10 is d-hK. In some embodiments, X10 is R5Me. In some embodiments, X10 is S5Me. In some embodiments, X10 is absent. In some embodiments, X11 is 2Nal or 6OH2Nal, each of which is an L-amino acid. In some embodiments, X11 is d2Nal or d6OH2Nal. In some embodiments, X11 is 2Nal. In some embodiments, X11 is d2Nal. In some embodiments, X11 is 6OH2Nal. In some embodiments, X11 is d6OH2Nal. In some embodiments, X12 is aMeK, R5Me, S5Me, or THP, wherein the aMeK is an L- amino acid. In some embodiments, X12 is d-aMeK, R5Me, S5Me, or THP. In some embodiments, X12 is aMeK or THP. In some embodiments, X12 is R5Me or S5Me. In some embodiments, X12 is aMeK. In some embodiments, X12 is d-aMeK. In some embodiments, X12 is R5Me. In some embodiments, X12 is S5Me. In some embodiments, X12 is THP. In some embodiments, X13 is aMeK(N3), E, hC, hE, K(Ac), Q, R5H, S5H, R5Me, or S5Me, wherein the aMeK(N3), E, hC, hE, K(Ac), and Q are L-amino acids. In some embodiments, X13 is d-aMeK(N3), dE, d-hC, d-hE, dK(Ac), dQ, R5H, S5H, R5Me, or S5Me. In some embodiments, X13 is aMeK(N3), E, hC, hE, Q, R5H, S5H, R5Me, or S5Me. In some embodiments, X13 is E, hE, Q, R5H, S5H, R5Me, or S5Me. In some embodiments, X13 is E, hE, or Q. In some embodiments, X13 is aMeK(N3). In some embodiments, X13 is d-aMeK(N3). In some embodiments, X13 is E. In some embodiments, X13 is dE. In some embodiments, X13 is hC. In some embodiments, X13 is d-hC. In some embodiments, X13 is hE. In some embodiments, X13 is d-hE. In some embodiments, X13 is K(Ac). In some embodiments, X13 is dK(Ac). In some embodiments, X13 is Q. In some embodiments, X13 is dQ. In some embodiments, X13 is R5H. In some embodiments, X13 is S5H. In some embodiments, X13 is R5Me. In some embodiments, X13 is S5Me. In some embodiments, X14 is D, hE, N, R5H, or S5H, wherein the D, hE, and N are L- amino acids. In some embodiments, X14 is dD, d-hE, dN, R5H, or S5H. In some embodiments, X14 is D or N. In some embodiments, X14 is R5H or S5H. In some embodiments, X14 is D. In some embodiments, X14 is dD. In some embodiments, X14 is hE. In some embodiments, X14 is d- hE. In some embodiments, X14 is N. In some embodiments, X14 is dN. In some embodiments, X14 is R5H. In some embodiments, X14 is S5H. In some embodiments, X15 is 3Pya or N, each of which is an L-amino acid. In some embodiments, X15 is d3Pya or dN. In some embodiments, X15 is 3Pya. In some embodiments, X15 is N. In some embodiments, X15 is d3Pya. In some embodiments, X15 is dN. In some embodiments, X16 is N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(iBu)Gly, Sar, or absent. In some embodiments, X16 is N(3AmBenzyl)Gly, Sar, or absent. In some embodiments, X16 is Sar or absent. In some embodiments, X16 is N(3AmBenzyl)Gly. In some embodiments, X16 is N(Cyclohexyl)Gly. In some embodiments, X16 is N(iBu)Gly. In some embodiments, X16 is Sar. In some embodiments, X16 is absent. In some embodiments, R2 is CONH2. In some embodiments, R2 is CONH(PEG3a). In some embodiments, X6 is absent, and X7, X8, X9, and X10 are not absent. In some embodiments, X6 and X7 are absent, and X8, X9, and X10 are not absent. In some embodiments, X6, X7, and X8 are absent, and X9 and X10 are not absent. In some embodiments, X6, X7, X8, and X9 are absent, and X10 is not absent. In some embodiments, X6, X7, X8, X9, and X10 are absent. In some embodiments, the peptide contains one linkage selected from the group consisting of a linkage between R1 and X13, a linkage between R1 and X14, a linkage between X8 and X12, a linkage between X9 and X13, a linkage between X10 and X13, and a linkage between X10 and X14. In some embodiments, the peptide contains a linkage between R1 and X13. In some embodiments, the linkage between R1 and X13 has a structure selected from the following: In some embodiments, the peptide contains a linkage between R1 and X14. In some embodiments, the linkage between R1 and X14 has a structure selected from the following: In some embodiments, the peptide contains a linkage between X8 and X12. In some embodiments, the linkage between X8 and X12 has a structure selected from the following: In some embodiments, the peptide contains a linkage between X9 and X13. In some embodiments, the linkage between X9 and X13 has a structure selected from the following: In some embodiments, the peptide contains a linkage between X10 and X13. In some embodiments, the linkage between X10 and X13 has the following structure : . AEF – E. In some embodiments, the peptide contains a linkage between X10 and X14. In some embodiments, the linkage between X10 and X14 has a structure selected from the following: In some embodiments, the peptide comprises an amino acid sequence selected from any of the following formulas: R1-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III-A), R1-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III-B), R1-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III-C), R1-X10-X11-X12-X13-X14-X15-X16-R2 (III-D), and R1-X11-X12-X13-X14-X15-X16-R2 (III-E), or a pharmaceutically acceptable salt thereof. In some embodiments, the peptide comprises the amino acid sequence of Formula (III- A): R1-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III-A) or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO; X7 is 7MeW or absent; 739659: NTT-4251PC X8 is Aib, K(Ac) or absent; X9 is aMePra, hC(pXyl), K, RS5, S5H, R5Me, S5Me, or absent; X10 is 4OMeF, AEF, F, hK, R5Me, S5H, or absent; X11 is 2Nal or 6OH2Nal; 5 X12 is aMeK or THP; X13 is aMeK(N3), E, hC, hE, Q, R5H, S5H, R5Me, or S5Me; X14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is N(3AmBenzyl)Gly, Sar, or absent; and 10 R2 is CONH2. In some embodiments, the peptide comprises the amino acid sequence of Formula (III- B): R1-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III-B) or a pharmaceutically acceptable salt thereof, wherein: 15 R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO; X8 is Aib, K(Ac) or absent; X9 is K, R5H, S5H, S5Me, S5Me, or absent; X10 is AEF, hK, R5H, S5H, or absent; X11 is 2Nal or 6OH2Nal; 20 X12 is aMeK or THP; X13 is E, hE, Q, R5H, S5H, R5Me, or S5Me; X14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is Sar; and 25 R2 is CONH2. In some embodiments, the peptide comprises the amino acid sequence of Formula (III- C): R1-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III-C), or a pharmaceutically acceptable salt thereof, wherein: 30 R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO; X9 is K, R5H, S5H, R5Me, S5Me, or absent; X10 is AEF, hK, R5H, S5H, or absent; X11 is 2Nal or 6OH2Nal; X12 is aMeK or THP; 35 X13 is E, hE, Q, R5H, S5H, R5Me, or S5Me; 216 X14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is Sar; and R2 is CONH2. In some embodiments, the peptide comprises the amino acid sequence of Formula (III- D): R1-X10-X11-X12-X13-X14-X15-X16-R2 (III-D) or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO; X10 is AEF, hK, R5H, S5H, or absent; X11 is 2Nal or 6OH2Nal; X12 is THP; X13 is E, hE, or Q; X14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is Sar; and R2 is CONH2. In some embodiments, the peptide comprises the amino acid sequence of Formula (III- E): R1-X11-X12-X13-X14-X15-X16-R2 (III-E) or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, or 8Aoc; X11 is 2Nal or 6OH2Nal; X12 is THP; X13 is E, hE, or Q; X14 is D or N; X15 is 3Pya; X16 is Sar; and R2 is CONH2. The present disclosure further provides a peptide having an amino acid sequence according to any one of SEQ ID NOS: 137-174, as shown in Table 4, or a pharmaceutically acceptable salt thereof. Table 4. Example Peptides
In the peptide sequences shown above, where a number in parenthesis follows a particular residue, that residue is linked to another residue in the sequence that is denoted with the same number. For example, in the sequence MeCO-hLys(2)-2Nal-THP-Q-D(2)-3Pya-Sar- CONH2 (SEQ ID NO: 152), the hLys(2) residue is linked to the D(2) residue. In yet another aspect, the present disclosure provides a peptide of any one of SEQ ID NOS: 175-215, as shown in Table 5, or a pharmaceutically acceptable salt thereof. Table 5. Example Peptides
In the peptide sequences shown above, where a number in parenthesis follows a particular residue, that residue is linked to another residue in the sequence that is denoted with the same number. For example, in the sequence MeCO-r-Pen(3)-N-T-7BrW-K(Ac)-Pen(3)-AEF- 2Nal-THP-E-N-THP-CONH2 (SEQ ID NO: 215), the two Pen(3) residues are linked to one another. In some embodiments, the present disclosure provides a peptide described herein provided the peptide retains activity as an inhibitor of interleukin-23 receptor. Methods of Synthesis The compounds described herein may be synthesized by many techniques that are known to those skilled in the art. In some aspects, the present disclosure provides a method of chemically synthesizing a peptide of the present disclosure. In some embodiments, a portion of the peptide is recombinantly synthesized, instead of being chemically synthesized. In some aspects, methods of producing a peptide further include cyclizing the peptide precursor after the constituent subunits have been attached. In particular aspects, cyclization is accomplished via any of the various methods described herein. The present disclosure further describes synthesis of compounds described herein. In some aspects, one or more of the amino acid residues or amino acid monomers are lipidated and then covalently attached to one another to form a peptide of the disclosure. In some aspects, one or more of the amino acid residues or amino acid monomers are covalently attached to one another and lipidated at an intermediate oligomer stage before attaching additional amino acids and cyclization to form a peptide of the disclosure. In some aspects, a cyclic peptide is synthesized and then lipidated to form a compound of the disclosure. Illustrative synthetic methods are described in the Examples. Pharmaceutical Compositions The present disclosure further relates to a pharmaceutical composition comprising an IL-23R inhibitor described herein. In particular, the present disclosure includes pharmaceutical compositions comprising one or more peptides of the present disclosure and a pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutically acceptable carrier, diluent or excipient may be a solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. The pharmaceutical compositions may be administered orally, parenterally, intracisternally, intravaginally, intraperitoneally, intrarectally, topically (as by powders, ointments, drops, suppository, or transdermal patch), by inhalation (such as intranasal spray), ocularly (such as intraocularly) or buccally. The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal and intraarticular injection and infusion. Accordingly, in certain embodiments, the compositions are formulated for delivery by any of these routes of administration. A pharmaceutical composition may be formulated for and administered orally. A pharmaceutical composition may be formulated for and administered parenterally. The IL-23R inhibitors of the present disclosure may be prepared and/or formulated as pharmaceutically acceptable salts and/or other forms thereof or when appropriate in neutral form. Pharmaceutically acceptable salts are non-toxic salts of a neutral form of a compound that possess the desired pharmacological activity of the neutral form. These salts may be derived from inorganic or organic acids or bases. For example, a compound that contains a basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006. The present disclosure relates to pharmaceutical compositions comprising an IL-23R inhibitor described herein or pharmaceutically acceptable salts, isomers, or a mixture thereof, in which one or more hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium. Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled peptides of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. When used in at least one of the treatments or delivery systems described herein, a peptide inhibitor of the present disclosure may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form. The total daily usage of the IL-23R inhibitor and compositions of the present disclosure can be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including: a) the disorder being treated and the severity of the disorder; b) activity of the specific compound employed; c) the specific composition employed, the age, body weight, general health, sex and diet of the patient; d) the time of administration, route of administration, and rate of excretion of the specific peptide inhibitor employed; e) the duration of the treatment; f) drugs used in combination or coincidental with the specific peptide inhibitor employed, and like factors well known in the medical arts. The compositions may conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Techniques and compositions generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. Non-Invasive Detection of Intestinal Inflammation The IL-23R inhibitors of the present disclosure may be used for detection, assessment and diagnosis of intestinal inflammation by microPET imaging, wherein the peptide inhibitor is labeled with a chelating group or a detectable label, as part of a non-invasive diagnostic procedure. In certain embodiments, an IL-23R inhibitor of the present disclosure is conjugated with a bifunctional chelator. In certain embodiments, an IL-23R inhibitor of the present disclosure is radiolabeled. The labeled IL-23R inhibitor is then administered to a subject orally or rectally. In certain embodiments, the IL-23R inhibitor is included in drinking water. Following uptake of the IL-23R inhibitor, microPET imaging may be used to visualize inflammation throughout the subject’s bowels and digestive track. Methods of Treatment and Uses The present disclosure relates to methods for treating a subject afflicted with a condition or indication associated with IL-23 or IL-23R activity (e.g., activation of the IL-23/IL-23R signaling pathway), wherein the method comprises administering to the subject an IL-23R inhibitor disclosed herein. In one aspect, the present disclosure provides a method for treating a subject afflicted with a condition or indication characterized by aberrant or dysregulated IL-23 or IL-23R activity or signaling, comprising administering to the subject a peptide inhibitor of the present disclosure in an amount sufficient to inhibit (partially or fully) binding of IL-23 to an IL- 23R in the subject. The inhibition of IL-23 binding to IL-23R may occur in particular organs or tissues of the subject, e.g., the stomach, small intestine, large intestine/colon, intestinal mucosa, lamina propria, Peyer’s Patches, mesenteric lymph nodes, or lymphatic ducts. The present disclosure relates to methods comprising providing a peptide inhibitor described herein to a subject in need thereof. The subject in need thereof may be a subject that has been diagnosed with or has been determined to be at risk of developing a disease or disorder associated with IL-23/IL-23R. The subject may be a mammal. The subject may be, in particular, a human. The disease or disorder to be treated by treatment with an IL-23R inhibitor of the present disclosure may be an inflammatory disease or disorder, an autoimmune inflammation diseases or disorder, and/or related disorders, including multiple sclerosis, asthma, rheumatoid arthritis, inflammation of the gut, inflammatory bowel diseases (IBDs), juvenile IBD, adolescent IBD, Crohn’s disease, ulcerative colitis, sarcoidosis, Systemic Lupus Erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, or psoriasis. In particular, the disease or disorder may be psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, Palmo-Plantar Pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, acne ectopica, ulcerative colitis, Crohn’s disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis/esophagitis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich Syndrome, pouchitis, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin- dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral- associated enteropathy, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft versus host disease. The present disclosure provides a method or use of an IL-23R inhibitor for treating an inflammatory disease or disorder in a subject in need thereof that includes administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present disclosure, a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising an IL-23 inhibitor of the present disclosure. The present disclosure provides a method or use of an IL-23R inhibitor for treating an autoimmune disease or disorder in a subject in need thereof that includes administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present disclosure, a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising an IL-23 inhibitor of the present disclosure. The present disclosure provides a method or use of an IL-23R inhibitor for treating an autoimmune inflammation disease or disorder in a subject in need thereof that includes administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present disclosure, a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising an IL-23 inhibitor of the present disclosure. Suitable inflammatory diseases, autoimmune inflammation diseases, and/or related disorders for treatment with a compound or pharmaceutically acceptable salt thereof, or a composition of the present disclosure, may include, but are not limited to inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA) and the like. The inflammatory disease to be treated may be inflammatory bowel disease (IBD), Crohn’s disease, or ulcerative colitis. The inflammatory disease to be treated may be selected from psoriasis or psoriatic arthritis. The inflammatory disease to be treated may be psoriasis The inflammatory disease to be treated may be psoriatic arthritis. The inflammatory disease to be treated may be IBD. The inflammatory disease to be treated may be Crohn’s disease. The inflammatory disease to be treated may be ulcerative colitis. Production of IL-23 is enriched in the intestine, where it is believed to play a key role in regulating the balance between tolerance and immunity through T-cell-dependent and T-cell- independent pathways of intestinal inflammation through effects on T-helper 1 (Th1) and Th17- associated cytokines, as well as restraining regulatory T-cell responses in the gut, favoring inflammation. In addition, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel diseases (IBDs), further establishing the critical role of the IL-23 pathway in intestinal homeostasis. Peptides and methods for specific targeting of the IL-23R from the luminal side of the gut may provide therapeutic benefit to IBD patients suffering from local inflammation of the intestinal tissue. Accordingly, the present disclosure also provides a method of treating or preventing inflammatory bowel disease (IBD), Crohn’s disease (CD), or ulcerative colitis (UC), in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a peptide of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein comprising an IL-23 inhibitor. In some embodiments, the method is for treating or preventing inflammatory bowel disease (IBD). In some embodiments, the method is for treating or preventing Crohn’s disease (CD). In some embodiments, the method is for treating or preventing ulcerative colitis (UC). Psoriasis, a chronic skin disease affecting about 2%-3% of the general population has been shown to be mediated by the body’s T cell inflammatory response mechanisms. IL-23 is one of several interleukins implicated as a key player in the pathogenesis of psoriasis, purportedly by maintaining chronic autoimmune inflammation via the induction of interleukin- 17, regulation of T memory cells, and activation of macrophages. Expression of IL-23 and IL- 23R has been shown to be increased in tissues of patients with psoriasis, and antibodies that neutralize IL-23 showed IL-23-dependent inhibition of psoriasis development in animal models of psoriasis. Orally bioavailable peptide inhibitors of IL-23 may provide both a non-steroidal treatment option for patients with mild to moderate psoriasis and treatment for moderate to severe psoriasis that does not require delivery by infusion. Accordingly, the present disclosure also provides a method of treating or preventing psoriasis (PsO) or psoriatic arthritis (PsA) in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a peptide of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein comprising an IL-23 inhibitor. In some embodiments, the method is for treating or preventing psoriasis (PsO). In some embodiments, the method is for treating or preventing psoriatic arthritis (PsA). The present disclosure further relates to a method of selectively inhibiting IL-23 or IL- 23R signaling (or the binding of IL-23 to IL-23R) in a subject (e.g., in a subject in need thereof), comprising administering to the subject a peptide inhibitor of the IL-23R described herein. In some embodiments, the present disclosure includes and provides a method of selectively inhibiting IL-23 or IL-23R signaling (or the binding of IL-23 to IL-23R) in the GI tract of a subject (e.g., a subject in need thereof), comprising providing to the subject a peptide inhibitor of the IL-23R of the present disclosure by oral administration. The exposure of GI tissues (e.g., small intestine or colon) to the administered peptide inhibitor may be at least 10-fold, at least 20- fold, at least 50-fold, or at least 100-fold greater than the exposure (level) in the blood. In particular embodiments, the present disclosure includes a method of selectively inhibiting IL23 or IL23R signaling (or the binding of IL23 to IL23R) in the GI tract of a subject (e.g., a subject in need thereof), comprising providing to the subject a peptide inhibitor, wherein the peptide inhibitor does not block the interaction between IL-6 and IL-6R or antagonize the IL-12 signaling pathway. In a further related embodiment, the present disclosure provides a method of inhibiting GI inflammation and/or neutrophil infiltration to the GI, comprising providing to a subject in need thereof a peptide inhibitor of the present disclosure. In some embodiments, methods of the present disclosure comprise providing a peptide inhibitor of the present disclosure (i.e., a first therapeutic agent) to a subject (e.g., a subject in need thereof) in combination with a second therapeutic agent. In certain embodiments, the second therapeutic agent is provided to the subject before and/or simultaneously with and/or after the peptide inhibitor is administered to the subject. In particular embodiments, the second therapeutic agent is an anti-inflammatory agent. In certain embodiments, the second therapeutic agent is a non- steroidal anti-inflammatory drug, steroid, or immune modulating agent. In certain embodiments, the method comprises administering to the subject a third therapeutic agent. In certain embodiments, the second therapeutic agent is an antibody that binds IL-23 or IL-23R. The present disclosure also relates to methods of inhibiting IL-23 binding to an IL-23R on a cell, comprising contacting the IL-23R with a peptide inhibitor of the receptor disclosed herein. The cell may be a mammalian cell. The method may be performed in vitro or in vivo. Inhibition of binding may be determined by a variety of routine experimental methods and assays known in the art. The present disclosure relates to methods of inhibiting IL-23 signaling by a cell, comprising contacting the IL-23R with a peptide inhibitor described herein. In certain embodiments, the cell is a mammalian cell. In particular embodiments, the method is performed in vitro or in vivo. In particular embodiments, the inhibition of IL-23 signaling may be determined by measuring changes in phospho-STAT3 levels in the cell. Examples The following examples are not intended to limit the scope of the present disclosure, but rather to provide guidance to the skilled artisan to prepare and use the peptides, compositions, and methods of the present disclosure. While particular aspects of the present disclosure are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the disclosure. Some abbreviations useful in describing the disclosure are defined below in the following tables. Herein and throughout the application, the following abbreviations may be used. Table 6. N-Terminal Modification Abbreviations
Table 7. C-Terminal Modification Abbreviations The amino acid structures provided in Table 8, below, are presented without stereochemical indicators at the alpha carbon; however, it is to be understood that these amino acids occur as either the L-amino acid or the D-amino acid. For example, “Dap” may be present in the peptides of the instant disclosure as the L-stereoisomer: ., or as the D-stereoisomer (e.g., when referred to as “dap,” “dDap,” or “D-Dap”): . Table 8. Monomer Abbreviations Example 1: General Procedure for Solid-Phase Synthesis of Peptides Peptide were chemically synthesized using optimized 9-fluorenylmethoxy carbonyl (Fmoc) solid phase peptide synthesis protocols. For C-terminal amides, Rink-amide MBHA resin was used. The side chain protecting groups were as follows: Lys: iv-dde; d-Arg: Pbf; Thr, Glu: O-tButyl; Asn, Pen, Cys, aMeCys: Trityl; AEF: Boc. For coupling, a two to five-fold excess of a solution containing Fmoc amino acid, HATU and DIEA (1:0.95:2) in DMF was added to swelled resin for 1 to 32 hours. Double coupling is employed when coupling 2Nal, K(Ac), Fmoc-4-Br-L-HomoAla-OH. Fmoc protecting group removal was achieved by treatment with a DMF, piperidine (4:1) solution for 30 min. Trt protecting group on aMeCys removal was achieved by treatment with trifluoroacetic acid, triisopropylsilane and DCM (2.5:2.5:95) solution for 3min*10 times. For thioether cyclization, a solution containing DIEA (5eq) in DMF was added to swelled resin for 1h* 2 times. iv-dde protecting group on Lys removal was achieved by treatment with 3%hydrazine hydrate in DMF solution for 20 min*3 times. The cycles are repeated until the full-length peptide is obtained. Certain materials and reagents are listed below. General procedure for cleavage of peptides off resin Side chain deprotection and cleavage of the peptides was achieved by stirring the dry resin in a solution of trifluoroacetic acid, water, DTT and tri-isopropylsilane (90:2.5:5:2.5) for 3 hours. The mixture was then filtered and cold methyl tert-butyl ether (MTBE) was added to the combined filtrate to precipitate the peptide. The resulting mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The pellet was lyophilized to provide the linear peptide. General procedure for cyclization To effect cyclization of thiol-containing residues, iodine solution in MeOH (0.1M) was added to a solution of the linear peptide (20% MeCN/H2O (1mmol/L)) drop-wise until a yellow color persisted. After about 2h, analysis by LCMS showed that the linear peptide was no longer present. The excess iodine was quenched by the addition of 1M Na2S2O3 in water (turned colorless instantly). General procedure for purification of peptides Purification of the peptides was achieved using reverse-phase high performance liquid chromatography (RP-HPLC). Purification of the cyclized peptides was achieved using preparative RP-HPLC with a C18 column with a flow rate of 20-250 mL/min. Separation was achieved using gradients of buffer B in A (Buffer A: 0.075% TFA in water; Buffer B: ACN). (Note 1). Analysis was performed using a C18 column with a flow rate of 1 mL/min (Note 2). Note 1: Preparative HPLC Methods Prep. HPLC Method A: Description: Mobile Phase: 0.075% TFA in water (solvent A) and acetonitrile (solvent B) Column: YMC-Actus Triart C18, 250*30 mm, 5 um, 120Å column; Flow Rate: 20 mL/min; Wavelength: UV 220nm&254nm; Oven Tem. Room temperature Note 2: Analytical HPLC Method: Mobile Phase: 0.1% TFA in water (solvent A) and 0.1%TFA in acetonitrile (solvent B), using the elution gradient 10%-80% (solvent B) over 0.9 minutes and using the elution gradient 80%-90% for 0.6 minutes at a flow rate of 1.0 ml/min; Column: Xbridge C18,3.5um,2.1*30mm; Wavelength: UV 220nm&254nm; Column temperature: 30℃; MS ionization: ESI Example 2: Synthesis of SEQ ID NO: 106
The peptide was synthesized using standard Fmoc chemistry. 1) DMF and MBHA Resin (0.20 mmol, 0.60 g, sub: 0.33 mmol/g) were combined in a vessel, and the resin was allowed to swell for two hours. 2) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 3) The resin was then drained and washed with DMF for 30 seconds*5 times. 4) Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds before addition of a solution of HATU and DIEA in DMF. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or tetrachlor color test, and upon completion, the resin was washed with DMF 5 times. Once peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum. Monitoring method: 1. Ninhydrin test: A: 5% ninhydrin /EtOH; B: 80% phenol /EtOH; C: pyridine 2. Tetrachlor color test: A: 2% tetrachlor/ DMF; B: 2% aldehyde/ DMF 110oC for 3min Peptide Cleavage: 1) To the flask containing the side chain protected peptide at room temperature was added 30 mL cleavage buffer (5.0% DTT /2.5% H2O /2.5% TIS /90%TFA), and mixture was stirred for 3 hrs. 2) The mixture was filtered and washed with 5 mL TFA. The combined filtrate was triturated with cold methyl tertbutyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. 3) The residue was lyophilized to give intermediate 1a (380 mg, 89.1%yield, crude) Peptide Cyclization and Purification: Crude peptide intermediate 1a (380 mg, 0.178 mmol) was dissolved in 20% MeCN /H2O (200 mL). To a stirred solution of the peptide was added the iodine solution in MeOH (0.1M, 1.5 mL) drop-wise until the color of the solution remains yellow. After ~2h LCMS showed the reaction was complete. Excess iodine was quenched by the addition of 1M Na2S2O3 in water (15 uL) (turned colorless instantly). Then was dded 10-20 mL of MeCN to decrease turbidity. The solution was purified by Prep-HPLC (A: 0.075% TFA in H2O, B: ACN) (Note 1: Method A) to give the peptide of SEQ ID NO: 106(63.6 mg, 99.4% purity, 15.0% yield for this step; over all yield: 13.4%) obtained as white solid. Analysis was performed using a C18 column with a flow rate of 1 mL/min (Note 2). LCMS Summary: Method: 10-80-3min-1.5.amx, retention time: 1.432 min, calculated MW: 2169.31, observed MW: 1064.7[(M+2H)/2]. Example 3: Synthesis of SEQ ID NO: 214
The peptide was synthesized using standard Fmoc chemistry. 1) DMF and MBHA Resin (0.30 mmol, 0.96 g, sub: 0.31 mmol/g) were combined in a vessel, and the resin was allowed to swell for two hours. 2) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 3) The resin was then drained and washed with DMF for 30 seconds*5 times. 4) Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds before addition of a solution of HATU and DIEA in DMF. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or tetrachlor color test, and upon completion, the resin was washed with DMF 5 times. Once peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum. Monitoring method: 1. Ninhydrin test: A: 5% ninhydrin /EtOH; B: 80% phenol /EtOH; C: pyridine 2. Tetrachlor color test: A: 2% tetrachlor/ DMF; B: 2% aldehyde/ DMF 110oC for 3min Peptide Cleavage: 1) To the flask containing the side chain protected peptide at room temperature was added 30 mL cleavage buffer (5.0% DTT /2.5% H2O /2.5% TIS /90%TFA), and mixture was stirred for 3 hrs. 2) The mixture was filtered and washed with 5 mL TFA. The combined filtrate was triturated with cold methyl tertbutyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. 3) The residue was lyophilized to give intermediate 2a (450 mg, 74.4% yield, crude) Peptide Cyclization and Purification: Crude peptide intermediate 2a (450 mg, 0.223 mmol) was dissolved in 20% MeCN /H2O (300 mL). To a stirred solution of the peptide was added the iodine solution in MeOH (0.1M, 1.5 mL) drop-wise until the color of the solution remains yellow. After ~2h LCMS showed the reaction was complete. Excess iodine was quenched by the addition of 1M Na2S2O3 in water (15 uL) (turned colorless instantly). Then was added 10-20 mL of MeCN to decrease turbidity. The solution was purified by Prep-HPLC (A: 0.075% TFA in H2O, B: ACN) (Note 1: Method A) to give the peptide of SEQ ID NO: 214 (38.3 mg, 98.42% purity, 7.16% yield for this step; over all yield: 5.33%) obtained as white solid. Analysis was performed using a C18 column with a flow rate of 1 mL/min (Note 2). LCMS Summary: Method: 10-80-3min-1.5_P2.amx, retention time: 1.506 min, calculated MW: 2012.27, observed MW: 1006.8[(M+2H)/2]. Example 4: Synthesis of SEQ ID NO: 210
The peptide was synthesized using standard Fmoc chemistry.
1) DMF and MBHA Resin (0.3 mmol, 1.3 g, sub: 0.23 mmol/g) were combined in a vessel, and the resin was allowed to swell for two hours. 2) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min.
3) The resin was then drained and washed with DMF for 30 seconds *5 times. 4) Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds before addition of a solution of HATU and DIEA in DMF. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or tetrachlor color test, and upon completion, the resin was washed with DMF 5 times. Once peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum. Monitoring method: 1. Ninhydrin test: A: 5% ninhydrin /EtOH; B: 80% phenol /EtOH; C: pyridine 2. Tetrachlor color test: A: 2% tetrachlor/ DMF; B: 2% aldehyde/ DMF 110oC for 3min Synthetic method for thioether cyclization: Coupling of Fmoc-4-Br-L-HomoAla-OH. After de-protection, the resin was washed with 20 mL of DMF (5x0.1 min) followed by addition of 1.5 mL of Fmoc-4-Br-L-HomoAla-OH in DMF (400 mM) and 1.5 mL of coupling reagent HOAT in DMF (400 mM) and DIC (92 uL). The coupling reaction was mixed for 16hrs and then washed with 20 mL of DMF (5x0.1 min). The coupling was repeated one more time for 16~32hrs. After completing the coupling reaction, the resin was washed with 30 mL of DMF (3x0.1 min). De-Trt of aMeCys: The resin was washed with 30 mL of DMF (5x0.1 min) and DCM (5x0.1 min) followed by addition of 2.5% TFA and 2.5%TIS in DCM (20 mL) (the reaction solution changed from orange to colorless). The resin was then washed with DCM, 5% DIEA in DMF and DMF 3 times Thioether cyclization on resin: The resin was washed with 30 mL of DMF (5x0.1 min) followed by addition of DIEA (5 eq) in DMF (50 mL). The suspension was mixed for 1h. Cleavage test and LCMS showed the reaction had finished. After completing the coupling reaction, the resin was washed with 30 mL of DMF (3x0.1 min). Peptide Cleavage: 1) To the flask containing the side chain protected peptide at room temperature was added 30 mL cleavage buffer (5.0% DTT /2.5% H2O /2.5% TIS /90%TFA), and mixture was stirred for 3 hrs. 2) The mixture was filtered and washed with 5 mL TFA. The combined filtrate was triturated with cold methyl tertbutyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. 3) The residue was lyophilized to give the crude product (450 mg, 81.6% yield, crude) Peptide Purification: Crude peptide (450 mg) was purified by Prep-HPLC (A: 0.075% TFA in H2O, B: ACN) (Note 1: Method A) to give the peptide of SEQ ID NO: 210 (60.4 mg, 99.3% purity, 9.6% yield) obtained as white solid. Analysis was performed using a C18 column with a flow rate of 1 mL/min (Note 2). LCMS Summary: Method: 10-80-2min-1.5_P2.amx, retention time: 1.522 min, calculated MW: 1838.05, observed MW: 919.7[(M+2H)/2]. Example 5: Synthesis of SEQ ID NO: 208
The peptide was synthesized using standard Fmoc chemistry. 1) DMF and MBHA Resin (0.6 mmol, 2.6 g, sub: 0.23 mmol/g) were combined in a vessel, and the resin was allowed to swell for two hours. 2) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 3) The resin was then drained and washed with DMF for 30 seconds*5 times. 4) Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds before addition of a solution of HATU and DIEA in DMF. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or tetrachlor color test, and upon completion, the resin was washed with DMF 5 times. Once peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum. Monitoring method: 1. Ninhydrin test: A: 5% ninhydrin /EtOH; B: 80% phenol /EtOH; C: pyridine 2. Tetrachlor color test: A: 2% tetrachlor/ DMF; B: 2% aldehyde/ DMF 110oC for 3min Synthetic method for thioether cyclization: Coupling of Fmoc-4-Br-L-HomoAla-OH. After de-protection, the resin was washed with 20 mL of DMF (5x0.1 min) followed by addition of 1.5 mL of Fmoc-4-Br-L-HomoAla-OH in DMF (400 mM) and 1.5 mL of coupling reagent HOAT in DMF (400 mM) and DIC (92 uL). The coupling reaction was mixed for 16hrs and then washed with 20 mL of DMF (5x0.1 min). The coupling was repeated one more time for 16~32hrs. After completing the coupling reaction, the resin was washed with 30 mL of DMF (3x0.1 min). De-Trt of aMeCys: The resin was washed with 30 mL of DMF (5x0.1 min) and DCM (5x0.1 min) followed by addition of 2.5% TFA and 2.5%TIS in DCM (20 mL) (the reaction solution changed from orange to colorless). The resin was then washed with DCM, 5% DIEA in DMF and DMF 3 times Thioether cyclization on resin: The resin was washed with 30 mL of DMF (5x0.1 min) followed by addition of DIEA (5 eq) in DMF (50 mL). The suspension was mixed for 1h. Cleavage test and LCMS showed the reaction had finished. After completing the coupling reaction, the resin was washed with 30 mL of DMF (3x0.1 min). Peptide Cleavage: 1) To the flask containing the side chain protected peptide at room temperature was added 30 mL cleavage buffer (5.0% DTT /2.5% H2O /2.5% TIS /90%TFA), and mixture was stirred for 3 hrs. 2) The mixture was filtered and washed with 5 mL TFA. The combined filtrate was triturated with cold methyl tertbutyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. 3) The residue was lyophilized to give the crude product (0.9 g, 75.2% yield, crude) Peptide Purification: Crude peptide 0.9 g was purified by Prep-HPLC (A: 0.075% TFA in H2O, B: ACN) (Note 1: Method A) to give the peptide of SEQ ID NO: 208 (64.4 mg, 98.4% purity, 4.52% yield) obtained as white solid. Analysis was performed using a C18 column with a flow rate of 1 mL/min (Note 2). LCMS Summary: Method: 10-80-2min-1.5_P2.amx, retention time: 1.300 min, calculated MW: 1994.23, observed MW: 998.2[(M+2H)/2]. Example 6: Synthesis of SEQ ID NO: 30
The peptide was synthesized using standard Fmoc chemistry. 1) DMF and MBHA Resin (0.20 mmol, 0.60 g, sub: 0.33 mmol/g) were combined in a vessel, and the resin was allowed to swell for two hours. 2) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 3) The resin was then drained and washed with DMF for 30 seconds*5 times. 4) Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds before addition of a solution of HATU and DIEA in DMF. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or tetrachlor color test, and upon completion, the resin was washed with DMF 5 times. Once peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum. Monitoring method: 1. Ninhydrin test: A: 5% ninhydrin /EtOH; B: 80% phenol /EtOH; C: pyridine 2. Tetrachlor color test: A: 2% tetrachlor/ DMF; B: 2% aldehyde/ DMF 110oC for 3min Peptide Cleavage: 1) To the flask containing the side chain protected peptide at room temperature was added 30 mL cleavage buffer (5.0% DTT /2.5% H2O /2.5% TIS /90%TFA), and mixture was stirred for 3 hrs. 2) The mixture was filtered and washed with 5 mL TFA. The combined filtrate was triturated with cold methyl tertbutyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. 3) The residue was lyophilized to give the intermediate 5a (400 mg, 94% yield, crude) Peptide Cyclization and Purification: Crude peptide intermediate 5a (400 mg, 0.189 mmol) was dissolved in 20% MeCN /H2O (200 mL). To a stirred solution of the peptide was added the iodine solution in MeOH (0.1M, 3.5 mL) drop-wise until the color of the solution remains yellow. After ~2h LCMS showed the reaction was complete. Excess iodine was quenched by the addition of 1M Na2S2O3 in water (15 uL) (turned colorless instantly). Then was added 10-20 mL of MeCN to decrease turbidity. The solution was purified by Prep-HPLC (A: 0.075% TFA in H2O, B: ACN) (Note 1: Method A) to give the peptide of SEQ ID NO: 30 (99.6 mg, 99.1% purity, 22.3% yield for this step; over all yield: 21.0%) obtained as white solid. Analysis was performed using a C18 column with a flow rate of 1 mL/min (Note 2). LCMS Summary: Method: 10-80-2min-1.5_P2.amx, retention time: 1.324 min, calculated MW: 2114.45, observed MW: 1058.3[(M+2H)/2]. Example 7: Synthesis of SEQ ID NO: 107
The peptide was synthesized using standard Fmoc chemistry. 1) DMF and MBHA Resin (0.20 mmol, 0.60 g, sub: 0.33 mmol/g) were combined in a vessel, and the resin was allowed to swell for two hours. 2) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 3) The resin was then drained and washed with DMF for 30 seconds*5 times. 4) Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds before addition of a solution of HATU and DIEA in DMF. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine/DMF was added and the suspension was mixed for 30 min. 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or tetrachlor color test, and upon completion, the resin was washed with DMF 5 times. Once peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum. Monitoring method: 1. Ninhydrin test: A: 5% ninhydrin /EtOH; B: 80% phenol /EtOH; C: pyridine 2. Tetrachlor color test: A: 2% tetrachlor/ DMF; B: 2% aldehyde/ DMF 110oC for 3min Synthetic method for removal of ivDde protecting group: Deprotection of ivDde on Lys: The resin was washed with 50 mL of DMF (5x0.1 min) followed by addition of 3% hydrazine hydrate in DMF (50 mL). The reaction was allowed to proceed for 20 (ninhydrin color reaction) before the resin was washed with DMF 5 times. Peptide Cleavage: 1) To the flask containing the side chain protected peptide at room temperature was added 30 mL cleavage buffer (5.0% DTT /2.5% H2O /2.5% TIS /90%TFA), and mixture was stirred for 3 hrs. 2) The mixture was filtered and washed with 5 mL TFA. The combined filtrate was triturated with cold methyl tertbutyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. 3) The residue was lyophilized to give the intermediate 6a (350 mg, 80.5% yield, crude) Peptide Cyclization and Purification: Crude peptide intermediate 6a (350 mg, 0.161 mmol) was dissolved in 20% MeCN /H2O (200 mL). To a stirred solution of the peptide was added the iodine solution in MeOH (0.1M, 1.5 mL) drop-wise until solution remains yellow. After ~2h LCMS showed the reaction was complete. Excess iodine was quenched by the addition of 1M Na2S2O3 in water (15 uL) (turned colorless instantly). Then was added 10-20 mL of MeCN to decrease turbidity. The solution was purified by Prep-HPLC (A: 0.075% TFA in H2O, B: ACN) (Note 1: Method A) to give the peptide of SEQ ID NO: 107 (76.1 mg, 97.04% purity, 19.1% yield for this step; over all yield: 15.4%) obtained as white solid. Analysis was performed using a C18 column with a flow rate of 1 mL/min (Note 2). LCMS Summary: Method: 10-80-3min-1.5.amx, retention time: 1.439 min, calculated MW: 2169.31, observed MW: 1085.3[(M+2H)/2]. Example 8: IL23R Reporter Assay Compounds were serially diluted in 100% (v/v) DMSO) and plated using an Echo acoustic dispenser (Labcyte) into 1536-well non-treated black assay plates (Corning # 9146). 3 µL of HEK293 cells containing IL-23R, IL-12R ^1 and a firefly luciferase reporter gene driven by a STAT-inducible promoter (Promega) were added to the plates (4000 cells/well), followed by 3 µL of 10 ng/mL IL-23 (equivalent to EC90 concentration). After 5h at 37 ^C, 5% CO2, 95% relative humidity, cells were placed at 20 ^C and treated with BioGlo reagent (Promega) according to the Manufacturer’s instructions. Luminescence was measured on a Pherastar FSX (BMG LabTech). Data were normalized to IL-23 treatment (0% inhibition) and 30 µM of control inhibitor (100% inhibition), and IC50 values were determined using a 4-parameter Hill equation. Data for example compounds are shown below. A: IC50 < 0.01 ^M; B: 0.01 ^M ≤ IC50 < 0.1 ^M; C: 0.1 ^M ≤ IC50 < 1 ^M; D: 1 ^M ≤ IC50 ND: Not determined Table 9. IL-23 Binding Data Example 9: PBMC pSTAT3 Assay Cryopreserved peripheral blood mononuclear cells (PBMCs) from healthy donors were thawed and washed twice in ImmunoCult-XF T cell expansion medium (XF-TCEM) supplemented with CTL anti-aggregate wash. The cells were counted, resuspended at 2-6x105 cells per mL XF-TCEM supplemented with penicillin/streptomycin and 100 ng/mL IL-1β (BioLegend, 579404), and cultured in tissue culture flasks coated with anti-CD3 (eBioscience, 16-0037-85 or BD Pharmingen, 555329) at 37oC in 5% CO2. On day 4 of culture, PBMCs were collected, washed twice in RPMI-1640 supplemented with 0.1% BSA (RPMI-BSA), and incubated in RPMI-BSA in upright tissue culture flasks for ~4 hours at 37oC in 5% CO2. Following this ‘starvation,’ a total of 6x104 cells in 30 µL RPMI-BSA was transferred into each well of a 384-well plate pre-spotted with peptide or DMSO. The cells were incubated for 30 minutes prior to the addition of IL-23 at a final concentration of 5 ng/mL. The cells were stimulated with cytokine for 30 minutes at 37oC in 5% CO2, transferred onto ice for 10 minutes, and lysed. Cell lysates were stored at -80°C until phosphorylated STAT3 was measured using the phospho-STAT panel kit (Meso Scale Discovery, K15202D). Results are provided below. A: IC50 < 0.01 nM; B: 0.01 nM ≤ IC50 < 0.1 nM; C: 0.1 nM ≤ IC50 < 1 nM; D: 1 nM ≤ IC50 < 10 nM; E: 10 nM ≤ IC50 < 100 nM; F: 100 nM ≤ IC50; ND: Not determined Table 10. PBMC pSTAT3 Assay Results While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims

CLAIMS What is claimed is: 1. A peptide of Formula (I), comprising the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I), or a pharmaceutically acceptable salt thereof, wherein: X3-X4-X5-X6 is selected from the group consisting of: X4–N–T, dR–X4–N–T, X4–dN–aMeT, X4–N–aMeT, dA–dN–dT, X4–b3hN–T, X4–N–b3hT, dE–X4–N–T, dR–X4–A–A, dR–X4–A–T, dR–X4–dN–dT, dR–X4–dN–T, dR–X4–N–A, dR–X4–N–dT, and R–X4–N–T, wherein X4 is an amino acid that is optionally linked to the amino acid at X9; X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–K(Ac)–X9–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–X9–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–X9–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–X9–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–X9–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–X9–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–X9–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–X9–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–X9–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–X9–AEF–2Nal–THP, 7MeW–A–X9–A–2Nal–THP, 7MeW–A–X9–AEF(G)–2Nal–THP, 7MeW–A–X9–AEF–2Nal–THP, 7MeW–b3hK–X9–AEF–2Nal–THP, 7MeW–b3hQ–X9–AEF–2Nal–THP, 7MeW–b3hQ–X9–AEF–b3hF–THP, 7MeW–dK(Ac)–X9–AEF–2Nal–THP, 7MeW–K(Ac)–X9–A–2Nal–THP, 7MeW–K(Ac)–X9–A–A–THP, 7MeW–K(Ac)–X9–AEF–2Nal–A, 7MeW–K(Ac)–X9–AEF–2Nal–Aib, 7MeW–K(Ac)–X9–AEF–b3hF–THP, 7MeW–K(Ac)–X9–APF–2Nal–THP, 7MeW–K(Ac)–X9–b3hY–2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–X9–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–X9–YCF2H–2Nal–THP, A–A–X9–A–A–THP, A–A–X9–AEF–2Nal–THP, A–K(Ac)–X9–AEF–A–THP, b3hW–K(Ac)–X9–AEF–2Nal–THP, b3hW–K(Ac)–X9–AEF–b3hF–THP, b3hW–K(Ac)–X9–b3hY–2Nal–THP, d7MeW–dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–X9–AEF–2Nal–THP, F–K(Ac)–X9–AEF–F–THP, L–K(Ac)–X9–AEF–2Nal–THP, L–K(Ac)–X9–AEF–L–THP, 7MeW–K(Ac)–X9–AEF–F–THP, and 7MeW–K(Ac)–X9–AEF–L–THP, wherein X9 is and amino acid that is optionally linked to the amino acid at X4; X13-X14-X15-X16 is selected from the group consisting of: E–N–3Pya–Sar, K(Ac)–N–3Pya–Sar, A–N–3Pya–Sar, b3hE–N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N–L–Sar, K(Ac)–N–5MePyridinAla–Sar, and R–N–3Pya–Sar; wherein no more than two of the following are true: X3-X4-X5-X6 is Abu–N–T, X3-X4-X5-X6 is C–N–T, X3-X4-X5-X6 is Pen–N–T, X3-X4-X5-X6 is dR–Abu–N–T, X3-X4-X5-X6 is dR–C–N–T, X3-X4-X5-X6 is dR–Pen–N–T, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–C–AEF–2Nal–THP, X13-X14-X15-X16 is E–N–3Pya–Sar, and X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar.
2. The peptide of claim 1, wherein no more than two of the following are true: X3-X4-X5-X6 is Abu–N–T, X3-X4-X5-X6 is aMeC–N–T, X3-X4-X5-X6 is C–N–T, X3-X4-X5-X6 is Pen–N–T, X3-X4-X5-X6 is dR–Abu–N–T, X3-X4-X5-X6 is dR–aMeC–N–T, X3-X4-X5-X6 is dR–C–N–T, X3-X4-X5-X6 is dR–Pen–N–T, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–C–AEF–2Nal–THP, X13-X14-X15-X16 is E–N–3Pya–Sar, and X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar.
3. The peptide of claim 1 or claim 2, wherein: X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; and X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3)
4. The peptide of any one of claims 1-3, wherein: X3-X4-X5-X6 is selected from the group consisting of: Abu–N–T, C–N–T, Pen–N–T, dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, Pen–N–b3hT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR–Pen–dN–T, dR–Pen–N–A, dR–Pen–N–dT, and R–Pen–N–T; X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW–dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, A–A–Pen–A–A–THP, A–A–Pen–AEF–2Nal–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, d7MeW–dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–2Nal–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, and 7MeW–K(Ac)–Pen–AEF–L–THP, X13-X14-X15-X16 is selected from the group consisting of: E–N–3Pya–Sar, K(Ac)–N–3Pya–Sar, A–N–3Pya–Sar, b3hE–N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N–L–Sar, K(Ac)–N–5MePyridinAla–Sar, and R–N–3Pya–Sar; wherein no more than two of the following are true: X3-X4-X5-X6 is Abu–N–T, X3-X4-X5-X6 is C–N–T, X3-X4-X5-X6 is Pen–N–T, X3-X4-X5-X6 is dR–Abu–N–T, X3-X4-X5-X6 is dR–C–N–T, X3-X4-X5-X6 is dR–Pen–N–T, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–C–AEF–2Nal–THP, X13-X14-X15-X16 is E–N–3Pya–Sar, and X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar; and wherein the Abu, C, or Pen in X3-X4-X5-X6 is optionally linked to the aMeC, C, or Pen in X7-X8-X9-X10-X11-X12 via a disulfide or thioether bond.
5. The peptide of any one of claims 1-4, comprising the amino acid sequence of Formula (I- A1): R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I-A1), or a pharmaceutically acceptable salt thereof, wherein: R1 is MeCO or EtCO.
6. The peptide of any one of claims 1-4, comprising the amino acid sequence of Formula (I- A2): X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (I-A2), or a pharmaceutically acceptable salt thereof, wherein: R2 is CONH2.
7. The peptide of any one of claims 1-6, comprising the amino acid sequence of Formula (I- A3): R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (I-A3), or a pharmaceutically acceptable salt thereof, wherein: R1 is MeCO or EtCO; and R2 is CONH2.
8. The peptide of any one of claims 1-7, wherein no more than one of the following is true: X3-X4-X5-X6 is Abu–N–T, X3-X4-X5-X6 is C–N–T, X3-X4-X5-X6 is Pen–N–T, X3-X4-X5-X6 is dR–Abu–N–T, X3-X4-X5-X6 is dR–C–N–T, X3-X4-X5-X6 is dR–Pen–N–T, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–Pen–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, X7-X8-X9-X10-X11-X12 is 7MeW–K(Ac)–C–AEF–2Nal–THP, X13-X14-X15-X16 is E–N–3Pya–Sar, and X13-X14-X15-X16 is K(Ac)–N–3Pya–Sar.
9. The peptide of any one of claims 4-8, wherein the Abu, C, or Pen in X3-X4-X5-X6 is linked to aMeC, C, or Pen in X7-X8-X9-X10-X11-X12 via a disulfide or thioether bond.
10. The peptide of any one of claims 1-9, wherein X3-X4-X5-X6 is selected from the group consisting of: Abu–N–T, C–N–T, dR–Abu–N–T, dR–C–N–T, Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, Pen–N–b3hT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR–Pen–dN–T, dR–Pen–N–A, dR–Pen–N–dT, and R–Pen–N–T.
11. The peptide of any one of claims 1-10, wherein X3-X4-X5-X6 is selected from the group consisting of: Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, Pen–N–b3hT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR–Pen–dN–T, dR–Pen–N–A, dR–Pen–N–dT, and R–Pen–N–T.
12. The peptide of any one of claims 1-9, wherein X3-X4-X5-X6 is selected from the group consisting of: Abu–N–T, C–N–T, Pen–N–T, Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–b3hN–T, and Pen–N–b3hT.
13. The peptide of any one of claims 1-9, wherein X3-X4-X5-X6 is selected from the group consisting of: dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, dA–dN–dT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR–Pen–dN–T, dR–Pen–N–A, dR–Pen–N–dT, and R–Pen–N–T.
14. The peptide of any one of claims 1-9, wherein X3-X4-X5-X6 is selected from the group consisting of: Pen–N–T, dR–Pen–N–T, Pen–b3hN–T, Pen–N–b3hT, dE–Pen–N–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, dR–Pen–dN–T, dR–Pen–N–A, dR–Pen–N–dT, and R–Pen–N–T.
15. The peptide of any one of claims 1-9, wherein X3-X4-X5-X6 is selected from the group consisting of: Abu–N–T, C–N–T, dR–Abu–N–T, dR–C–N–T, Abu–dN–aMeT, Abu–N–aMeT, and dA–dN–dT.
16. The peptide of any one of claims 1-9, wherein X3-X4-X5-X6 is selected from the group consisting of: Abu–N–T, C–N–T, Pen–N–T, dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, Abu–N–aMeT, Pen–N–b3hT, dE–Pen–N–T, dR–Pen–N–A, dR–Pen–N–dT, and R–Pen–N–T.
17. The peptide of any one of claims 1-9, wherein X3-X4-X5-X6 is selected from the group consisting of: Abu–dN–aMeT, dA–dN–dT, Pen–b3hN–T, dR–Pen–A–A, dR–Pen–A–T, dR–Pen–dN–dT, and dR–Pen–dN–T.
18. The peptide of any one of claims 1-9, wherein X3-X4-X5-X6 is selected from the group consisting of: Abu–N–T, C–N–T, Pen–N–T, dR–Abu–N–T, dR–C–N–T, dR–Pen–N–T, Pen–b3hN–T, dE–Pen–N–T, dR–Pen–A–T, dR–Pen–dN–T, and R–Pen–N–T.
19. The peptide of any one of claims 1-9, wherein X3-X4-X5-X6 is selected from the group consisting of: Abu–dN–aMeT, Abu–N–aMeT, dA–dN–dT, Pen–N–b3hT, dR–Pen–A–A, dR–Pen–dN–dT, dR–Pen–N–A, and dR–Pen–N–dT.
20. The peptide of any one of claims 1-19, wherein X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW–dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, A–A–Pen–A–A–THP, A–A–Pen–AEF–2Nal–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, d7MeW–dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–2Nal–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, and 7MeW–K(Ac)–Pen–AEF–L–THP.
21. The peptide of any one of claims 1-20, wherein X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW–dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, A–A–Pen–A–A–THP, A–A–Pen–AEF–2Nal–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, d7MeW–dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–2Nal–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, and 7MeW–K(Ac)–Pen–AEF–L–THP.
22. The peptide of any one of claims 1-19, wherein X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW–dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, and 7MeW–K(Ac)–Pen–AEF–L–THP,
23. The peptide of any one of claims 1-19, wherein X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP, A–A–Pen–A–A–THP, A–A–Pen–AEF–2Nal–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, d7MeW–dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–2Nal–THP, and L–K(Ac)–Pen–AEF–L–THP.
24. The peptide of any one of claims 1-19, wherein X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–2Nal–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, and 7MeW–K(Ac)–Pen–AEF–L–THP.
25. The peptide of any one of claims 1-19, wherein X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–A–Pen–A–2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW–dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, A–A–Pen–A–A–THP, A–A–Pen–AEF–2Nal–THP, and d7MeW–dK(Ac)–dA–dY–d2Nal–THP.
26. The peptide of any one of claims 1-19, wherein X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, A–A–Pen–A–A–THP, A–A–Pen–AEF–2Nal–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–2Nal–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, and 7MeW–K(Ac)–Pen–AEF–L–THP,
27. The peptide of any one of claims 1-19, wherein X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–aMeC–AEF–2Nal–THP, and d7MeW–dK(Ac)–dA–dY–d2Nal–THP.
28. The peptide of any one of claims 1-19, wherein X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW–dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, A–A–Pen–AEF–2Nal–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, F–K(Ac)–Pen–AEF–2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–2Nal–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, and 7MeW–K(Ac)–Pen–AEF–L–THP,
29. The peptide of any one of claims 1-19, wherein X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, A–A–Pen–A–A–THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, and d7MeW–dK(Ac)–dA–dY–d2Nal–THP.
30. The peptide of any one of claims 1-19, wherein X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–K(Ac)–aMeC–AEF–2Nal–THP, 7MeW–K(Ac)–C–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–THP, 7(3(1NMepip)pyraz)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3(6AzaInd1Me))W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–aMeC–AEF–2Nal–THP, 7(3NAcPh)W–K(Ac)–Pen–AEF(G)–2Nal–THP, 7(3NPyrazPh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(3NpyrlonePh)W–K(Ac)–Pen–AEF–2Nal–THP, 7(5(2(4OMePh)Pyr))W–K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxdeQuin8Me))W –K(Ac)–Pen–AEF–2Nal–THP, 7(6(2OxIquin))W –K(Ac)–Pen–AEF–2Nal–THP, 7(7(124TAZP))W–K(Ac)–Pen–AEF–2Nal–THP, 7(7(2OMeQuin))W–K(Ac)–Pen–AEF–2Nal–THP, 7MeW–A–Pen–A–2Nal–THP, 7MeW–A–Pen–AEF(G)–2Nal–THP, 7MeW–A–Pen–AEF–2Nal–THP, 7MeW–b3hK–Pen–AEF–2Nal–THP, 7MeW–b3hQ–Pen–AEF–2Nal–THP, 7MeW–dK(Ac)–aMeC–AEF–2Nal–THP, 7MeW–dK(Ac)–Pen–AEF–2Nal–THP, 7MeW–K(Ac)–Pen–A–2Nal–THP, 7MeW–K(Ac)–Pen–AEF–2Nal–A, 7MeW–K(Ac)–Pen–AEF–2Nal–Aib, 7MeW–K(Ac)–Pen–APF–2Nal–THP, 7MeW–K(Ac)–Pen–b3hY–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlAme2)–2Nal–THP, 7MeW–K(Ac)–Pen–F(4TzlG2)–2Nal–THP, 7MeW–K(Ac)–Pen–YCF2H–2Nal–THP, A–A–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–AEF–2Nal–THP, b3hW–K(Ac)–Pen–b3hY–2Nal–THP, F–K(Ac)–Pen–AEF–2Nal–THP, and L–K(Ac)–Pen–AEF–2Nal–THP.
31. The peptide of any one of claims 1-19, wherein X7-X8-X9-X10-X11-X12 is selected from the group consisting of: 7MeW–b3hQ–Pen–AEF–b3hF–THP, 7MeW–K(Ac)–Pen–A–A–THP, 7MeW–K(Ac)–Pen–AEF–b3hF–THP, A–A–Pen–A–A–THP, A–K(Ac)–Pen–AEF–A–THP, b3hW–K(Ac)–Pen–AEF–b3hF–THP, d7MeW–dK(Ac)–dA–dY–d2Nal–THP, F–K(Ac)–Pen–AEF–F–THP, L–K(Ac)–Pen–AEF–L–THP, 7MeW–K(Ac)–Pen–AEF–F–THP, and 7MeW–K(Ac)–Pen–AEF–L–THP,
32. The peptide of any one of claims 1-31, wherein X13-X14-X15-X16 is selected from the group consisting of: K(Ac)–N–3Pya–Sar, A–N–3Pya–Sar, b3hE–N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N–L–Sar, K(Ac)–N–5MePyridinAla–Sar, and R–N–3Pya–Sar.
33. The peptide of any one of claims 1-32, wherein X13-X14-X15-X16 is selected from the group consisting of: A–N–3Pya–Sar, b3hE–N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N–L–Sar, K(Ac)–N–5MePyridinAla–Sar, and R–N–3Pya–Sar.
34. The peptide of any one of claims 1-31, wherein X13-X14-X15-X16 is selected from the group consisting of: E–N–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, and E–N–L–Sar
35. The peptide of any one of claims 1-31, wherein X13-X14-X15-X16 is selected from the group consisting of: K(Ac)–N–3Pya–Sar, A–N–3Pya–Sar, b3hE–N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, K(Ac)–N–5MePyridinAla–Sar, and R–N–3Pya–Sar.
36. The peptide of any one of claims 1-31, wherein X13-X14-X15-X16 is selected from the group consisting of: E–N–3Pya–Sar, K(Ac)–N–3Pya–Sar, A–N–3Pya–Sar, b3hE–N–3Pya–Sar, dE–N–3Pya–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N–L–Sar, K(Ac)–N–5MePyridinAla–Sar, and R–N–3Pya–Sar.
37. The peptide of any one of claims 1-31, wherein X13-X14-X15-X16 is selected from the group consisting of: dE–dN–3Pya–Sar, E–A–3Pya–Sar, E–A–A–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, and E–F–3Pya–Sar.
38. The peptide of any one of claims 1-31, wherein X13-X14-X15-X16 is selected from the group consisting of: E–N–3Pya–Sar, K(Ac)–N–3Pya–Sar, A–N–3Pya–Sar, b3hE–N–3Pya–Sar, dE–dN–3Pya–Sar, dE–N–3Pya–Sar, E–A–3Pya–Sar, E–b3hN–3Pya–Sar, E–dN–3Pya–Sar, E–F–3Pya–Sar, and R–N–3Pya–Sar.
39. The peptide of any one of claims 1-31, wherein X13-X14-X15-X16 is selected from the group consisting of: E–A–A–Sar, E–N–A–Sar, E–N–b3hF–Sar, E–N–dK–bMeDTyr, E–N–L–Sar, and K(Ac)–N–5MePyridinAla–Sar.
40. The peptide of claim 1, having an amino acid sequence selected from the group consisting of SEQ ID NOS: 1-89.
41. A peptide of Formula (II), comprising the amino acid sequence: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (II), or a pharmaceutically acceptable salt thereof, wherein: R1 is an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker, or R1 is AEEP or MeCO; X3 is K or R, or absent, wherein the K is conjugated to a reactive handle, optionally via a linker; X4 is 4AminoPro, A, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra X5 is N or Q; X6 is 7MeW or T; X7 is 7MeW, T, or W; X8 is K(Ac) or Q; X9 is A, aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X10 is 2Nal or AEF; X11 is AEF or 2Nal; X12 is aMeK, K, N, or THP, wherein the K is conjugated to a reactive handle, optionally via a linker; X13 is E, K, or K(Ac), wherein the K is conjugated to an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker; X14 is L, 3Pya, or N; X15 is aMeK, 3Pya, L, or THP; X16 is K, Sar, or absent, wherein the K is conjugated to a second peptide, optionally via a linker; R2 is CONH2; wherein if R1 is biotin optionally bound to the rest of the peptide via a linker, then X13 is E or X15 is L; wherein the peptide has one linkage selected from the group consisting of: a linkage between AEEP at R1 and E at X13; a linkage between 4AminoPro at X4 and D, E, or hE at X9; a linkage between Abu at X4 and aMeC, C, or Pen at X9; a linkage between aG at X4 and aG at X9; a linkage between aMeC at X4 and aMeC, C, or Pen at X9; a linkage between C at X4 and aMeC, C, or Pen at X9; a linkage between Dap at R4 and D at R9; a linkage between Pen at R4 and aMeC, C, or Pen at R9; a linkage between Pen(oXyl) at R4 and Pen at R9; a linkage between Pen(mXyl) at R4 and Pen at R9; a linkage between Pen(pXyl) at R4 and Pen at R9; and a linkage between Pra at R4 and Dap(N3) at X9; provided that: (i) the peptide comprises at least one moiety selected from the group consisting of an albumin-binding moiety, biotin, an imaging agent, a second peptide, and a reactive handle; or (ii) the peptide has a linkage between AEEP at R1 and E at X13, between 4AminoPro at X4 and D at X9, between 4AminoPro at X4 and E at X9, between 4AminoPro at X4 and hE at X9, between aG at X4 and aG at X9, between Dap at R4 and D at R9, between Pen(mXyl) at R4 and Pen at R9, between Pen(mXyl) at R4 and Pen at R9, between Pen(pXyl) at R4 and Pen at R9, or between Pra at R4 and Dap(N3) at X9.
42. The peptide of claim 41, comprising the amino acid sequence of Formula (II-A): R1-X3-X4-N-T-X7-K(Ac)-X9-AEF-2Nal-X12-X13-N-X15-X16-R2 (II-A), or a pharmaceutically acceptable salt thereof, wherein: R1 is an albumin-binding moiety, an imaging agent, a second peptide, or a reactive handle, each of which is optionally bound to the rest of the peptide via a linker, or R1 is AEEP or MeCO; X3 is K or R, or absent, wherein the K is conjugated to a reactive handle, optionally via a linker; X4 is 4AminoPro, A, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra X7 is 7MeW or W; X9 is A, aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X12 is aMeK, K, or THP, wherein the K is conjugated to a reactive handle, optionally via a linker; X13 is E, K, or K(Ac), wherein the K is conjugated to an albumin-binding moiety, biotin, an imaging agent, a second peptide, or a reactive handle, optionally via a linker; X15 is 3Pya or L; X16 is K, Sar, or absent, wherein the K is conjugated to a second peptide, optionally via a linker; R2 is CONH2; wherein the peptide has one linkage selected from the group consisting of: a linkage between AEEP at R1 and E at X13; a linkage between 4AminoPro at X4 and D, E, or hE at X9; a linkage between Abu at X4 and aMeC, C, or Pen at X9; a linkage between aG at X4 and aG at X9; a linkage between aMeC at X4 and aMeC, C, or Pen at X9; a linkage between C at X4 and aMeC, C, or Pen at X9; a linkage between Dap at R4 and D at R9; a linkage between Pen at R4 and aMeC, C, or Pen at R9; a linkage between Pen(oXyl) at R4 and Pen at R9; a linkage between Pen(mXyl) at R4 and Pen at R9; a linkage between Pen(pXyl) at R4 and Pen at R9; and a linkage between Pra at R4 and Dap(N3) at X9; provided that: (i) the peptide comprises at least one moiety selected from the group consisting of an albumin-binding moiety, biotin, an imaging agent, a second peptide, and a reactive handle; or (ii) the peptide has a linkage between AEEP at R1 and E at X13, between 4AminoPro at X4 and D at X9, between 4AminoPro at X4 and E at X9, between 4AminoPro at X4 and hE at X9, between aG at X4 and aG at X9, between Dap at R4 and D at R9, between Pen(mXyl) at R4 and Pen at R9, between Pen(mXyl) at R4 and Pen at R9, between Pen(pXyl) at R4 and Pen at R9, or between Pra at R4 and Dap(N3) at X9.
43. The peptide of claim 41 or claim 42, or a pharmaceutically acceptable salt thereof, wherein the linker is a polyethylene glycol chain.
44. The peptide of any one of claims 41-43, or a pharmaceutically acceptable salt thereof, wherein the peptide comprises at least one moiety selected from the group consisting of an albumin-binding moiety, biotin, an imaging agent, a second peptide, and a reactive handle.
45. The peptide of any one of claims 41-44, or a pharmaceutically acceptable salt thereof, wherein the albumin-binding moiety is selected from the group consisting of diflunisal, indomethacin, 4-(p-iodophenyl)butyric acid, and Evans blue dye fragment.
46. The peptide of any one of claims 41-45, or a pharmaceutically acceptable salt thereof, wherein the albumin-binding moiety is diflunisal or 4-(p-iodophenyl)butyric acid.
47. The peptide of any one of claims 41-46, or a pharmaceutically acceptable salt thereof, wherein the imaging agent is a radioisotopically labeled polyethylene glycol chain, Cy5, or fluorescein (FITC).
48. The peptide of any one of claims 41-47, or a pharmaceutically acceptable salt thereof, wherein the reactive handle is an alkyne, an azide, or an α-halo carbonyl.
49. The peptide of any one of claims 41-48, or a pharmaceutically acceptable salt thereof, wherein the reactive handle is a pentynoic acid, an α-iodo carbonyl, an α-bromo carbonyl, or an α-chloro carbonyl.
50. The peptide of any one of claims 41-49, or a pharmaceutically acceptable salt thereof, wherein the peptide has a linkage between AEEP at R1 and E at X13, between 4AminoPro at X4 and D at X9, between 4AminoPro at X4 and E at X9, between 4AminoPro at X4 and hE at X9, between aG at X4 and aG at X9, between Dap at R4 and D at R9, between Pen(mXyl) at R4 and Pen at R9, between Pen(mXyl) at R4 and Pen at R9, between Pen(pXyl) at R4 and Pen at R9, or between Pra at R4 and Dap(N3) at X9.
51. The peptide of any one of claims 41-50, or a pharmaceutically acceptable salt thereof, wherein the peptide has a linkage between 4AminoPro at X4 and E at X9.
52. The peptide of any one of claims 41-50, or a pharmaceutically acceptable salt thereof, wherein the peptide has a linkage between 4AminoPro at X4 and hE at X9.
53. The peptide of any one of claims 41-50, or a pharmaceutically acceptable salt thereof, wherein the peptide has a linkage between AEEP at R1 and E at X13.
54. The peptide of any one of claims 41-50, or a pharmaceutically acceptable salt thereof, wherein the peptide has a linkage between Dap at R4 and D at R9.
55. The peptide of any one of claims 41-50, or a pharmaceutically acceptable salt thereof, wherein the peptide has a linkage between Pra at R4 and Dap(N3) at X9.
56. The peptide of claim 41, having an amino acid sequence selected from the group consisting of SEQ ID NOS: 90-136.
57. A peptide of Formula (III), comprising the amino acid sequence: R1-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III), or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, MeCO, or PyE; X6 is 3OHPro, Aib, T, or absent; X7 is 7MeW or absent; X8 is Aib, K(Ac), K(NMeAc), R5Me, S5Me, or absent; X9 is Aib, aMePra, hC(pXyl), K, Pen, R5H, S5H, R5Me, S5Me, or absent; X10 is 4OMeF, AEF, F, hK, R5H, S5H, or absent; X11 is 2Nal or 6OH2Nal; X12 is aMeK, R5Me, S5Me, or THP; X13 is aMeK(N3), E, hC, hE, K(Ac), Q, R5H, S5H, R5Me, or S5Me; X14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(iBu)Gly, Sar, or absent; and R2 is CONH2 or CONH(PEG3a); wherein: when X10 is absent, X6, X7, X8, and X9 are also absent, when X9 is absent, X6, X7, and X8 are also absent, when X8 is absent, X6 and X7 are also absent, and when X7 is absent X6 is also absent; wherein: when R1 is 5Ava, the 5Ava is linked to an E at X13 or an hE at X13; when R1 is 6Ahx, the 6Ahx is optionally linked to an E at X13 or an hE at X13; when R1 is 7Ahp, the 7Ahp is linked to an E at X13 or an hE at X13 or a D at X14; when R1 is 8Aoc, the 8Aoc is linked to an E at X13 an hE at X13; when R1 is bAla, the bAla is linked to an E at X13 or an hE at X13; when X8 is R5Me, the R5Me is linked to an R5Me or an S5Me at X12; when X8 is S5Me, the S5Me is linked to an R5Me or an S5Me at X12; when X9 is aMePra, the aMePra is linked to an aMeK(N3) at X13; when X9 is hC(pXyl), the hC(pXyl) is linked to an hC at X13; when X9 is K, the K is optionally linked to an E at X13 or an hE at X13; when X9 is R5H, the R5H is optionally linked to an R5H at X13, an S5H at X13, an R5Me at X13, or an S5Me at X13; when X9 is S5H, the S5H is optionally linked to an R5H at X13, an S5H at X13, an R5Me at X13, or an S5Me at X13; when X9 is R5Me, the R5Me is optionally linked to an R5H at X13, an S5H at X13, an R5Me at X13,or an S5Me at X13; when X9 is S5Me, the S5Me is optionally linked to an R5H at X13, an S5H at X13, an R5Me at X13,or an S5Me at X13; when X10 is AEF, the AEF is optionally linked to an E at X13 or an hE at X14; when X10 is hK, the hK is linked to a D at X14; when X10 is R5H, the R5H is linked to an R5H at X14 or an S5H at X14; when X10 is S5H, the S5H is linked to an R5H at X14 or an S5H at X14; when X12 is R5Me, the R5Me is linked to an R5Me at X8 or an S5Me at X8; when X12 is S5Me, the S5Me is linked to an R5Me at X8 or an S5Me at X8; when X13 is aMeK(N3), the aMeK(N3) is linked to an aMePra at X9; when X13 is E, the E is optionally linked to a 5Ava at R1, a 6Ahx at R1, a 7Ahp at R1, an 8Aoc at R1, a bAla at R1, a K at X9, or an AEF at X10; when X13 is hC, the hC is linked to an hC(pXyl) at X9; when X13 is hE, the hE is linked to a 5Ava at R1, a 6Ahx at R1, a 7Ahp at R1, an 8Aoc at R1, or a bAla at R1; when X13 is R5H, the R5H is optionally linked to an S5H at X9, an S5H at X9, an R5Me at X9, or an S5Me at X9; when X13 is S5H, the S5H is optionally linked to an S5H at X9, an S5H at X9, an R5Me at X9, or an S5Me at X9; when X13 is S5Me, the S5Me is optionally linked to an S5H at X9, an S5H at X9, an R5Me at X9, or an S5Me at X9; when X14 is D, the D is linked to a 7Ahp at R1 or an hK at X10; when X14 is hE, the hE is linked to an AEF at X10; when X14 is R5H, the R5H is linked to an R5H at X10 or an S5H at X10; and when X14 is S5H, the S5H is linked to an R5H at X10 or an S5H at X10; wherein: the peptide contains no more than one linkage selected from the group consisting of a linkage between R1 and X13, a linkage between R1 and X14, a linkage between X8 and X12, a linkage between X9 and X13, a linkage between X10 and X13, and a linkage between X10 and X14.
58. The peptide of claim 57, wherein the peptide contains one linkage selected from the group consisting of a linkage between R1 and X13, a linkage between R1 and X14, a linkage between X8 and X12, a linkage between X9 and X13, a linkage between X10 and X13, and a linkage between X10 and X14.
59. The peptide of claim 57 or claim 58, comprising the amino acid sequence of Formula (III-A): R1-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III-A) or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO; X7 is 7MeW or absent; X8 is Aib, K(Ac) or absent; X9 is aMePra, hC(pXyl), K, RS5, S5H, R5Me, S5Me, or absent; X10 is 4OMeF, AEF, F, hK, R5Me, S5H, or absent; X11 is 2Nal or 6OH2Nal; X12 is aMeK or THP; X13 is aMeK(N3), E, hC, hE, Q, R5H, S5H, R5Me, or S5Me; X14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is N(3AmBenzyl)Gly, Sar, or absent; and R2 is CONH2.
60. The peptide of any one of claims 57-59, comprising the amino acid sequence of Formula (III-B): R1-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III-B) or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO; X8 is Aib, K(Ac) or absent; X9 is K, R5H, S5H, S5Me, S5Me, or absent; X10 is AEF, hK, R5H, S5H, or absent; X11 is 2Nal or 6OH2Nal; X12 is aMeK or THP; X13 is E, hE, Q, R5H, S5H, R5Me, or S5Me; X14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is Sar; and R2 is CONH2.
61. The peptide of any one of claims 57-60, comprising the amino acid sequence of Formula (III-C): R1-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III-C) or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO; X9 is K, R5H, S5H, R5Me, S5Me, or absent; X10 is AEF, hK, R5H, S5H, or absent; X11 is 2Nal or 6OH2Nal; X12 is aMeK or THP; X13 is E, hE, Q, R5H, S5H, R5Me, or S5Me; X14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is Sar; and R2 is CONH2.
62. The peptide of any one of claims 57-61, comprising the amino acid sequence of Formula (III-D): R1-X10-X11-X12-X13-X14-X15-X16-R2 (III-D) or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, 8Aoc, bAla, or MeCO; X10 is AEF, hK, R5H, S5H, or absent; X11 is 2Nal or 6OH2Nal; X12 is THP; X13 is E, hE, or Q; X14 is D, hE, N, R5H, or S5H; X15 is 3Pya or N; X16 is Sar; and R2 is CONH2.
63. The peptide of any one of claims 57-62, comprising the amino acid sequence of Formula (III-E): R1-X11-X12-X13-X14-X15-X16-R2 (III-E) or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 6Ahx, 7Ahp, or 8Aoc; X11 is 2Nal or 6OH2Nal; X12 is THP; X13 is E, hE, or Q; X14 is D or N; X15 is 3Pya; X16 is Sar; and R2 is CONH2.
64. The peptide of claim 57, having an amino acid sequence selected from the group consisting of SEQ ID NOS: 137-174.
65. A peptide having an amino acid sequence selected from the group consisting of SEQ ID NOS: 175-215.
66. A peptide having an amino acid sequence selected from the group consisting of SEQ ID NOS: 216-223.
67. A pharmaceutical composition comprising a peptide of any one of claims 1-66, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
68. A method for treating a disease or disorder associated with Interleukin 23 (IL- 23)/Interleukin 23 Receptor (IL-23R), comprising administering to a subject in need thereof a therapeutically effective amount of a peptide of any one of claims 1-66 or a pharmaceutical composition of claim 67.
69. The method of claim 68, wherein the disease or disorder is selected from multiple sclerosis, asthma, rheumatoid arthritis, inflammation of the gut, inflammatory bowel diseases (IBDs), juvenile IBD, adolescent IBD, Crohn’s disease, ulcerative colitis, Celiac disease (nontropical Sprue), microscopic colitis, collagenous colitis, eosinophilic gastroenteritis/esophagitis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1, sarcoidosis, Systemic Lupus Erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, Palmo- Plantar Pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, acne ectopica, enteropathy associated with seronegative arthropathies, chronic granulomatous disease, glycogen storage disease type lb, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich Syndrome, pouchitis, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft versus host disease.
70. The method of claim 68, wherein the disease or disorder is selected from ulcerative colitis (UC), Crohn’s disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA).
EP24706605.3A 2023-01-16 2024-01-15 Peptide inhibitors of interleukin-23 receptor Pending EP4652180A2 (en)

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