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WO2025147479A1 - Inhibiteurs de fusion virale - Google Patents

Inhibiteurs de fusion virale Download PDF

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Publication number
WO2025147479A1
WO2025147479A1 PCT/US2025/010035 US2025010035W WO2025147479A1 WO 2025147479 A1 WO2025147479 A1 WO 2025147479A1 US 2025010035 W US2025010035 W US 2025010035W WO 2025147479 A1 WO2025147479 A1 WO 2025147479A1
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Prior art keywords
moiety
inhibitor
peptide
seq
peptide moiety
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PCT/US2025/010035
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English (en)
Inventor
Zachary Z. Brown
Pei Huo
Samaneh MESBAHI-VASEY
Jeffrey William SCHUBERT
Jason W. Skudlarek
Hua-Poo SU
Thomas J. Tucker
Kalpit A. Vora
Deeptak Verma
Abbas M. Walji
Chengwei WU
Zhe Wu
Elisabetta Bianchi
Tommaso FRATTARELLI
Federica NOVELLI
Federica TUCCI
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Merck Sharp and Dohme LLC
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Merck Sharp and Dohme LLC
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Publication of WO2025147479A1 publication Critical patent/WO2025147479A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/162—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • SARS-CoV severe acute respiratory syndrome coronavirus
  • the fusion process for SARS-CoV occurs at either the cell surface membrane or at the endosomal membrane.
  • the fusion process is mediated by the envelope S glycoprotein that is a type I transmembrane glycoprotein.
  • the envelope glycoprotein of class I viruses plays an important role in the fusion process for all human coronaviruses similarly to many other viruses including human immunodeficiency virus (HIV), Influenza, Ebola, Marburg, etc.
  • the key player in the infectivity process is the S protein consisting of two sub-units, S1 and S2.
  • S1 subunit binds the cellular receptor through its receptor-binding domain (RBD), followed by conformational changes in the S2 subunit, which allows the fusion peptide to insert into the host target cell membrane.
  • RBD receptor-binding domain
  • the heptad repeat 1 (HR1) region in the S2 subunit forms a homo-trimeric assembly, which exposes three conserved hydrophobic grooves on the surface that bind heptad repeat 2 (HR2).
  • a pre hairpin intermediate of this six-helix bundle (6-HB) core structure is formed during the fusion process and helps bring the viral and cellular membranes into close proximity for viral fusion and entry.
  • 6-HB six-helix bundle
  • the present disclosure is based upon the discovery that fusion between a viral membrane and a host cell membrane can be reduced by a compound that interrupts interaction of envelope glycoproteins (e.g., interaction between HR1 and HR2).
  • the present disclosure provides viral fusion inhibitors comprising a peptide moiety, a linker moiety, and a lipid moiety.
  • viral fusion inhibitors of the present disclosure provide pan-coronavirus activities.
  • a peptide moiety of a viral fusion inhibitor is based on in general the HR2 region of SARS-CoV-2.
  • a certain portion of the HR2 region when incorporated in a viral fusion inhibitor, may in fact provide more effective antiviral activities and/or pan-coronavirus activities.
  • the present disclosure is based, in part, on the insight that one or more mutations or substitutions in a peptide from the HR2 region can enhance antiviral potency.
  • the present disclosure describes certain features (e.g., conjugation chemistry between a peptide moiety and a linker moiety, conjugation chemistry between a linker moiety and a lipid moiety, and the length or physical properties of a linker moiety) of the viral fusion inhibitors, which may play an important role in antiviral potency and/or pan-coronavirus activity.
  • inhibitors of viral fusion comprising (i) a peptide moiety, (ii) a linker moiety, and (iii) a lipid moiety, wherein the linker moiety connects the C-terminal part of the peptide moiety to the lipid moiety, wherein the peptide moiety comprises at least ten contiguous amino acids of the heptad repeat 2 (HR2) domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and wherein the N-terminal part of the peptide moiety is PDVD as set forth in SEQ ID NO. 418.
  • HR2 heptad repeat 2
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • the peptide moiety comprises a peptide as set forth in SEQ ID NO:1, X 1 is P, and X 2 is D.
  • inhibitors of viral fusion comprising (i) a peptide moiety, (ii) a linker moiety, and a lipid moiety, wherein the linker moiety connects the C-terminal part of the peptide moiety to the lipid moiety, wherein the peptide moiety comprises at least ten contiguous amino acids of the heptad repeat 2 (HR2) domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and wherein the N-terminal part of the peptide moiety is PEVD as set forth in SEQ ID NO.
  • HR2 heptad repeat 2
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • the peptide moiety comprises a peptide as set forth in SEQ ID NO:1, X1 is P, and X2 is E.
  • inhibitors of viral fusion comprising (i) a peptide moiety, (ii) a linker moiety; and (iii) a lipid moiety, wherein the linker moiety connects the C-terminal part of the peptide moiety to the lipid moiety, wherein the peptide moiety comprises at least ten contiguous amino acids of the heptad repeat 2 (HR2) domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and wherein the N-terminal part of the peptide moiety is (2R,4S)Prot4OacOH-DVD.
  • HR2 heptad repeat 2
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • the peptide moiety comprises a peptide as set forth in SEQ ID NO:1, X1 is (2R,4S)Prot4OacOH, and X2 is D. [0011] In some embodiments, the peptide moiety comprises at least one amino acid that is different from the HR2 domain of SARS-CoV-2. [0012] In some embodiments, the peptide moiety comprises at least one amino acid that is not natural. [0013] In some embodiments, the peptide moiety further comprises C at the C-terminal part of the peptide moiety. In some embodiments, the peptide moiety further comprises CGSG as set forth in SEQ ID NO.421 at the C-terminal part of the peptide moiety.
  • the peptide moiety further comprises GGGSGGGGSG as set forth in SEQ ID NO.422 at the C- terminal part of the peptide moiety. In some embodiments, the peptide moiety further comprises GSGGGSGG as set forth in SEQ ID NO. 423 at the C-terminal part of the peptide moiety. In some embodiments, the peptide moiety further comprises KYEQYIG as set forth in SEQ ID NO. 424 at the C-terminal part of the peptide moiety. [0014] In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOs: 2-39.
  • the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOs: 3-39. In some embodiments, the peptide moiety comprise a peptide as set forth in SEQ ID NO: 40. In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOs: 279, 287, 288, 291, 292, 296, 300, 303, 308-376, 395-398, and 407-413. In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOs: 309, 389, 399, or 401-404.
  • the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOs: 377, 378, 405, 406, and 414-416.
  • the lipid moiety comprises cholesterol, tocopherol, or palmitate. In some embodiments, the lipid moiety comprises cholesterol.
  • the linker moiety is attached to the lipid moiety via an ether bond, an ester bond, a carbamate bond, or a triazole bond.
  • the linker 25856 moiety is attached to the lipid moiety via an ether bond. In some embodiments, the linker moiety is attached to the lipid moiety via an triazole bond.
  • the linker moiety comprises an amino acid. In some embodiments, the linker moiety is selected from the group consisting of compounds listed in Table 2. In some embodiments, the linker moiety comprises PEG12-C(propyl)-NH2, Ttds2-C(propyl)-NH2, Ttds3-C(propyl)-NH2, Ttds4-C(propyl)-NH2, Ttds2- Dab(triazole-propyl)-NH 2 , Ttds 3 -Dab(triazole-propyl)-NH 2 , Ttds 4 -Dab(triazole-propyl)-NH 2 , Ttds2-Orn(triazole-propyl)-NH2, or Ttds3-Orn(triazole-propyl)-NH2.
  • the inhibitor is selected from the group consisting of compounds listed in Table 3A.
  • the N-terminal part of the peptide moiety is acetylated.
  • the inhibitor further comprises a half-life extension moiety.
  • the half-life extension moiety comprises 4-(p-iodophenyl)butyric acid (4IPhBut).
  • the half-life extension moiety is attached to the N-terminal part of the peptide moiety.
  • the half-life extension moiety is selected from the group consisting of 4IPhBut-eK-Succinyl, 4IPhBut-eK-Succinyl-AEEA, 4IPhBut-eK- Succinyl-(AEEA)2, 4IPhBut-eK-Succinyl-(AEEA)3, and 4IPhBut-eK-Succinyl-GSGSG (SEQ ID NO: 425).
  • the peptide moiety has a Lys, D-Lys or Orn mutation, and the half-life moiety is attached to the mutation.
  • the peptide moiety has Lys in position 1168.
  • the peptide moiety comprise a peptide as set forth in SEQ ID NO: 407.
  • the half-life extension moiety is selected from the group consisting of 4IPhBut-eK-Succinyl, 4IPhBut-eK-Succinyl-AEEA, 4IPhBut-eK-Succinyl- (AEEA) 2 , and 4IPhBut-eK-Succinyl-(AEEA) 3 .
  • compositions comprising the inhibitor, or a pharmaceutically acceptable carrier or diluent.
  • inhibitors for use in a method of treatment or prevention of a subject are provided.
  • pan-coronavirus activity or pan- coronavirus potency refers to anti-viral activity against two or more of SARS-CoV-1 (i.e., the virus behind the 2002–2003 severe acute respiratory syndrome outbreak), mutant forms that the SARS-CoV-1 could adopt, SARS-CoV-2, mutant forms that the SARS-CoV-2 could adopt, and/or major lineages of coronavirus (e.g., sarbecoviruses that is the subgenus including all the SARS-like viruses, betacoronaviruses that is the larger branch of the family tree that counts the pathogen responsible for Middle East respiratory syndrome (MERS), some seasonal coronaviruses that cause the common cold).
  • SARS-CoV-1 i.e., the virus behind the 2002–2003 severe acute respiratory syndrome outbreak
  • mutant forms that the SARS-CoV-1 could adopt i.e., the virus behind the 2002–2003 severe acute respiratory syndrome outbreak
  • SARS-CoV-2 mutant forms that the SARS-CoV-2 could adopt
  • the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOS: 119-156. In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOS: 120-156. [0098] In some embodiments, the peptide moiety comprises a peptide as set forth in SEQ ID NO: 157. In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOS: 158-195. In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOS: 159-195.
  • the peptide moiety comprises a peptide as set forth in SEQ ID NO: 196. In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOS: 197-234. In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOS: 198-234. [0100] In some embodiments, the peptide moiety comprises a peptide as set forth in SEQ ID NO: 235. In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOS: 236-273.
  • the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOS: 237-273. [0101] In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOS: 274-350. [0102] In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOS: 351-394. [0103] In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in 368-416. [0104] In some embodiments, the N-terminal part of the peptide moiety is PDVD as set forth in SEQ ID NO.
  • the N-terminal part of the peptide moiety is PEVD as set forth in SEQ ID NO. 419. In some embodiments, the N-terminal part of the peptide moiety is (2R,4S)Prot4OacOH-DVD. [0105] In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOs: 310, 390, 400, or 402-405. [0106] In some embodiments, the peptide moiety is selected from the group consisting of peptides as set forth in SEQ ID NOs: 378, 379, 406, 407, and 415-417. 25856 Table 1.
  • Ttds 1-Amino-15-oxo-4,7,10-trioxa-14-azaoctadecan-18-oic acid
  • the linker moiety comprises Ttds2. In some embodiments, the linker moiety comprises Ttds3. In some embodiments, the linker moiety comprises Ttds4. In some embodiments, the linker moiety comprises 11-amino undecanoic acid (11-Aun). [0109] In some embodiments, the linker moiety comprises an amino acid. In some embodiments, the amino acid is selected from the group consisting of Cys, Glu (E), hGlu (hE), Orn, Lys (K), 2,4-Diaminobutyric Acid (Dab). [0110] In some embodiments, the amino acid in the linker moiety is not directly connected to the C-terminal part of the peptide moiety.
  • the lipid moiety comprises cholesterol.
  • the linker moiety and the lipid moiety is connected via an ether bond, an ester bond, a carbamate bond, or a triazole bond.
  • the linker moiety and the lipid moiety is connected via an ether bond.
  • the linker moiety and the lipid moiety is connected via an ester bond.
  • the linker moiety and the lipid moiety is connected via a carbamate bond.
  • the linker moiety and the lipid moiety is connected via a triazole bond.
  • the attachment of the lipid moiety via an ether bond may provide improved metabolic stability compared to an ester bond.
  • the metabolic stability is measured by a remaining time in mouse plasma.
  • the lipid moiety is connected to a side chain of the amino acid in the linker moiety.
  • the viral fusion inhibitor comprise a peptide moiety listed in Table 1, a linker moiety listed in Table 2, and a lipid moiety selected from the group consisting of cholesterol, tocopherol, and palmitate.
  • the viral fusion inhibitor comprises a compound listed in Table 3A. In some embodiments, the viral fusion inhibitor comprises a compound listed in Table 3B. 25856 [0117] In some embodiments, antiviral activity of the viral fusion inhibitors is characterized by a pseudo-type neutralization assay. In some embodiments, when a pseudo-type neutralization assay is performed similarly to Example 1, EC50 of the viral fusion inhibitors is about sub nanomolar range, about 1 digit nanomolar range, or about 2 digits nanomolar range. [0118] In some embodiments, the viral fusion inhibitors of the present disclosure exhibit pan- coronavirus activity or pan-coronavirus potency.
  • pan-coronavirus activity or pan-coronavirus potency is characterized by a pseudo-type neutralization assay.
  • EC50 of the viral fusion inhibitors exhibiting pan-coronavirus activity or pan-coronavirus potency is about sub nanomolar range, about 1 digit nanomolar range, or about 2 digits nanomolar range at least for two or more different types of coronavirus. Table 3A.
  • the inhibitor comprises a half-life extension moiety.
  • the half-life extension moiety comprises 4-(p-iodophenyl)butyric acid (4IPhBut).
  • the carboxylate group of 4IPhBut can be linked to amino groups on the side chains of various amino acids.
  • the half-life extension moiety is attached to the N-terminal part of the peptide moiety.
  • the half-life extension moiety is selected from the group consisting of 4IPhBut-eK-Succinyl, 4IPhBut-eK-Succinyl-AEEA, 4IPhBut-eK-Succinyl- 25856 (AEEA)2, 4IPhBut-eK-Succinyl-(AEEA)3, and 4IPhBut-eK-Succinyl-GSGSG (SEQ ID NO: 425).
  • the half-life extension moiety comprises 4IPhBut-eK-Succinyl.
  • the half-life extension moiety comprises 4IPhBut-eK-Succinyl-AEEA.
  • the half-life extension moiety comprises 4IPhBut-eK-Succinyl-(AEEA)2. In some embodiments, the half-life extension moiety comprises 4IPhBut-eK-Succinyl-(AEEA)3. In some embodiments, the half-life extension moiety comprises 4IPhBut-eK-Succinyl-GSGSG (SEQ ID NO: 425). [0123] The present disclosure encompasses the insight that Lys, D-Lys or Orn in a peptide moiety can be used to attach a half-life extension moiety. In some embodiments, the peptide moiety comprises a mutation to which the half-life moiety is attached.
  • one or more amino acids of the peptide moiety are substituted to Lys, D-Lys or Orn. In some embodiments, an amino acid of the peptide moiety is substituted to Lys. In some embodiments, the peptide moiety has Lys in position 1168. In some embodiments, the peptide moiety comprise a peptide as set forth in SEQ ID NO: 408.
  • the half-life extension moiety is selected from the group consisting of 4IPhBut-eK-Succinyl, 4IPhBut-eK-Succinyl-AEEA, 4IPhBut-eK-Succinyl-(AEEA)2, and 4IPhBut-eK-Succinyl-(AEEA)3.
  • the half-life extension moiety comprises 4IPhBut-eK-Succinyl.
  • the half-life extension moiety comprises 4IPhBut-eK-Succinyl-AEEA.
  • the half-life extension moiety comprises 4IPhBut-eK-Succinyl-(AEEA)2.
  • the half-life extension moiety comprises 4IPhBut-eK-Succinyl-(AEEA)3.
  • Dosing and Administration [0124] Further provided herein are dosing regimens and routes of administration for treating or preventing an infection using a viral fusion inhibitor.
  • the viral fusion inhibitor disclosed herein may be administered by doses administered intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscular, intracerebrally, intraspinally, or by inhalation.
  • the doses are administered intravenously.
  • the doses are administered subcutaneously.
  • the doses are administered orally.
  • the doses are nasally.
  • a provided viral fusion inhibitor is administered according to a dosing regimen sufficient to achieve a reduction in the degree and/or prevalence of symptoms of infection of a specified percentage of a population of patients to which the viral fusion inhibitor 25856 is administered.
  • the specified percentage of population of patients to which the viral fusion inhibitor was administered is at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 31 %, about 32%. about 33%.
  • administration of at least one provided composition comprising a viral fusion inhibitor according to a dosing regimen is sufficient to achieve a reduction in the degree and/or prevalence of infection of at least about 20% in at least about 50% of the population of patients to which the composition was administered. In some embodiments, administration of at least one composition according to a dosing regimen is sufficient to achieve a reduction in the degree and/or prevalence of infection of at least about 30% in at least about 50% of the population of patients to which the composition was administered. [0128] In some embodiments, at least one provided pharmaceutical composition comprising a viral fusion inhibitor is administered according to a dosing regimen sufficient to achieve a delay in the onset of symptoms of infection.
  • At least one provided composition is administered according to a dosing regimen sufficient to prevent the onset of one or more symptoms of infection.
  • a provided dosing regimen comprises or consists of a single dose.
  • a provided dosing regimen comprises or consists of multiple doses, separated from one another by intervals of time that may or may not vary.
  • a provided dosing regimen comprises or consists of dosing once every 20 years, once every 10 years, once every 5 years, once every 4 years, once every 3 years, once every 2 years, once per year, twice per year, 3 times per year, 4 times per year, 5 times per year, 6 times per year, 7 times per year, 8 times per year, 9 times per year, 10 times per year, 11 times per year, once per month, 25856 twice per month, three times per month, once per week, twice per week, three times per week, 4 times per week, 5 times per week, 6 times per week, daily, twice daily, 3 times daily, 4 times daily, 5 times daily, 6 times daily, 7 times daily, 8 times daily, 9 times daily, 10 times daily, 11 times daily, 12 times daily, or hourly.
  • a provided dosing regimen comprises or consists of an initial dose with one or more booster doses.
  • one or more booster doses are administered 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 1 month, 2 months, 6 months, 1 year, 2 years, 5 years, 10 years, or longer than 10 years after the initial dose.
  • an initial dose comprises a series of doses administered over a period of time.
  • an initial dose comprises a series of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or more doses administered at regular intervals, e.g., intervals that are close in time to one another, such as 5 minute intervals, 10 minute intervals, 15 minute intervals, 20 minute intervals, 25 minute intervals, 30 minute intervals, 45 minute intervals, hourly intervals, every 2 hours, etc.
  • a provided dosing regimen comprises or consists of administration of multiple doses over the course of the subject's entire lifespan.
  • a provided dosing regimen comprises administration of multiple doses over the course of several years (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100 years). In some embodiments, a provided dosing regimen comprises or consists of multiple doses over the course of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.
  • Pharmaceutical Compositions [0133] In yet another aspect, provided herein are pharmaceutical compositions comprising the therapeutic agents disclosed herein (e.g., a viral fusion inhibitor). [0134] In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • Examples of pharmaceutically acceptable carriers include buffers, such as phosphate, citrate, acetate, and other organic acids; antioxidants, such as ascorbic acid; low molecular weight (e.g., fewer than about 10 amino acid residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulin; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and/or nonionic surfactants, such as TWEEN TM , polyethylene glycol (PEG), and PLURONICS TM .
  • buffers such as phosphate, citrate, acetate, and other organic acids
  • kits comprising the therapeutic agents disclosed herein (e.g., a viral fusion inhibitor) or pharmaceutical compositions thereof, packaged into suitable packaging material.
  • a kit optionally includes a label or packaging insert that include a description of the components or instructions for use in vitro, in vivo, or ex vivo, of the components therein.
  • the kit further comprises instructions for administering to a human patient the viral fusion inhibitor.
  • the kit comprises: (a) one or more dosages of a viral fusion inhibitor; and (b) instructions for administering to a human patient the viral fusion inhibitor.
  • PEG 12 in the linker moiety was replaced with the following: 1 ) two or three units of Ttds (PepSP1793 and PepSP1794); 25856 2 ) a flexible but more hydrophobic GS-like units: (GGGS)2 (SEQ ID NO: 680) in PepSP2174 and (GGSG)2G-PEG2 (SEQ ID NO: 681) in PepSP2175; 3) a hydrophilic poly-Sarcosine polypeptoid, i.e., (Sar)10-PEG2 in PepSP2254; and/or 4) 7 residues from the HR2 of SARS-CoV-2 C-terminal sequence with or without PEG2 or PEG4 units (PepSP2253, PepSP2176, PepSP2177).
  • the amino acids used as conjugation points are Glu or homoGlu, with either 3 or 6 carbon spacers between the sidechain amide and the cholesterol moiety.
  • the compounds are generically represented by the structure shown in Figure 5. Also, several compounds using Orn as a conjugation point was also prepared, as detailed in Figure 6. The corresponding structures are listed in Table 20. Table 21. Exemplary viral fusion inhibitors ID SEQUENCE & Structure SEQ ID NO 25856 I D SEQUENCE & Structure SEQ ID NO Ac-PDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELG-PEG12-E(propyl-O- C d 9 554 T able 22.
  • the thioether bond was substituted with a triazole bond to perform conjugation between the linker moiety and the lipid moiety via a click chemistry reaction (see Figure 3).
  • the C-terminal cystine required for the conjugation was replaced with a Lys(N3) or Dab(N3) residues (i.e., (S)-2-(Fmoc-amino)-6-azido-hexanoic acid and (S)-2-(Fmoc-amino)-4- azido-butanoic acid), which reacts with a pentyn-O-cholesterol reagent yielding PepSP2172, PepSP2173, PepSP2424, and PepSP2430.
  • the replacement of the thioether bond by a triazole bond may provide more stability in formulation and improve its shelf-life compared to PepSP1545.
  • the results of the pseudo- neutralization assay revealed the achievement of constructs with excellent antiviral potency against CoV-2 and MERS similar to that of PepSP1545.
  • a series of compounds was prepared that contain carbamate-based linkages to the cholesterol instead of the ether linkages. The various carbamate structures prepared are shown in Figure 7 and the corresponding peptide sequences are detailed in Table 24. Table 25.
  • Example 9 Alternative chemistry for conjugation between the peptide moiety and the linker moiety
  • This example shows additional exemplary alternative chemistry for conjugating the lipid moiety.
  • a series of compounds was prepared, which comprises a Lys appended to the C- terminus of the peptide moiety with the linker moiety attached via the epsilon (side chain) nitrogen of the Lys amino acid.
  • a generic structure representing these varied compounds is shown in Figure 15. Specific structures and data are shown in Table 26. Table 27.
  • Ttds moieties were beneficial for manufacturing purposes, as they are more affordable than PEG moieties.
  • New sequences in Table 30 were prepared to combine newly identified point mutations and linkers with the triazole chemistry for cholesterol conjugation. T able 31.
  • the C-terminal Dab(N3) required for the conjugation was replaced with a Lys(N3) or Orn(N3) residues (i.e., (S)-2-(Fmoc-amino)-6- azido-hexanoic acid and (S)-2-(Fmoc-amino)-5-azido-pentanoic acid), and combined with 2 or 3 Ttds moieties, resulting in the compounds: PepSP2439, PepSP2440, PepSP2441, and PepSP2442.
  • a Lys(N3) or Orn(N3) residues i.e., (S)-2-(Fmoc-amino)-6- azido-hexanoic acid and (S)-2-(Fmoc-amino)-5-azido-pentanoic acid
  • Exemplary viral fusion inhibitors SEQ ID I D SEQUENCE & Structure NO 25856 SEQ ID I D SEQUENCE & Structure NO 25856 SEQ ID I D SEQUENCE & Structure NO . oV- 2, and MERS.
  • CoV-2 A549 CoV-2 Hela MERS P seudoneut EC50 - SARS2 D614G Pseudoneut EC50 - SARS2 D614G ID P d t EC50 i Hh7 25856
  • This example shows exemplary half-life extension of viral fusion inhibitors.
  • PepSP2430 was functionalized with Albutag using a Succinyl- eK(4IPhBut) building block.
  • Albutag was introduced at position 1168 and/or at the N-terminus.
  • Two different spacers were also tested to identify the optimal linker for PK extension: different number of AEEA units, moving from 0 to 3; and a flexible stretch of GSGSG residues (SEQ ID NO: 675).
  • the structures of the compounds are listed in Table 36.
  • Table 37 Exemplary viral fusion inhibitors SEQ ID I D SEQUENCE & Structure NO 25856 SEQ ID I D SEQUENCE & Structure NO oV- 2, and MERS.
  • Example 12 Live Virus Assay
  • This example shows exemplary live virus assays against several inhibitors.
  • Some inhibitors were tested in a number of varied live virus assays against several strains of CoV2 including WA1 (WT CoV2) and BA.5 (current Omicron variant). A small subset of inhibitors was tested against WA1, BA.2, BA2.12.1, BA.4, and BA.5, and the 25856 results are summarized in Table 38.
  • Example 13 Plasma stability and In vivo experiments with selected compounds 25856 Pharmacokinetics after IV and SC dosing [0288] Selected compounds were evaluated for pharmacokinetics after intravenous and subcutaneous dosing to mice. The pharmacokinetics of selected compounds were evaluated in mice or hamsters. For each study, the individual test compounds was administered to subjects in via a preselected route of administration which included intranasal (IN), intratracheal (IT), intravenous (IV), or subcutaneous (SC).
  • I intranasal
  • IT intratracheal
  • IV intravenous
  • SC subcutaneous
  • PepSP1141 demonstrated statistically significant reductions in viral load and viral RNA in this experiment.
  • 8-9 week-old K18-humanized ACE2 mice male and female were nasally inoculated with SARS CoV-2 virus strain USA-WA1/2020 (P4, Catalog#: NR-53873.9.2X10 5 TCID50/ml (Vero E6), Lot#:70039812); Virus titer 4.6x104 TCID50/ animal) on day zero.
  • the test compound was dosed intranasally on day 0 at 2 hours before infection, and once a day on days 1-3. Intranasal doing was performed as follows: 1 .
  • mice anaesthetized by isoflurane.
  • the positive-displacement pipette to the volume of material to be delivered. Load the tip with the inoculum (0.05 mL maximum volume). 3 . Hold the mouse upright at an approximate 30-degree angle. 4. Place the tip to the nares of the mouse. Slowly release the inoculum dropwise onto the nares making sure the entire drop is inhaled. 5 . Place mouse on its back in a clean cage and observe until the mouse is up and moving around the cage.
  • PepSP1141 demonstrated dose dependent, statistically significant reductions in viral load and viral RNA in this experiment. ⁇ Hamster antiviral efficacy at various SC doses with PepSP1545 with PepSP1141 as SC control
  • Male syrian hamsters were nasally inoculated with SARS CoV-2 virus strain USA- WA1/2020 (P4, Catalog#: NR-53873. 9.2x105 TCID50/ml (Vero E6), Lot#:70039812); Virus titer 4.6x10 4 TCID 50 /animal) on day zero.
  • PepSP1411 At a subcutaneous dose of 15 mg/kg, PepSP1411 exhibited slightly better plasma levels at 2 hours, 4 hours, and 8 hours compared to Compound X as shown in Figure 33. However, at 24 hours, PepSP1411 showed approximately 10 times higher plasma levels than Compound X. Compound Y was not detectable at any of the time points. [0303] A number of the animals were sacrificed and their lung exposures were determined using two methods of detection: LC-MS/MS, and ex vivo analysis of lung tissue using a pseudoneutralization bioassay. Both methods showed that the levels of PepSP1141 in the lung tissue were consistently higher than those demonstrated by Compound X. The levels of Compound Y were undetectable in the lung tissue. [0304] Furthermore, in the testing described in Example 1, PepSP1141 and the compounds disclosed herein exhibited greater potency and a wider range of activity against the coronavirus compared to Compound X and Compound Y.

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Abstract

La présente invention concerne des inhibiteurs de fusion virale, ainsi que l'utilisation de ces inhibiteurs de fusion virale dans le traitement ou la prévention d'une maladie infectieuse ou d'une infection.
PCT/US2025/010035 2024-01-04 2025-01-02 Inhibiteurs de fusion virale Pending WO2025147479A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7151163B2 (en) * 2003-04-28 2006-12-19 Sequoia Pharmaceuticals, Inc. Antiviral agents for the treatment, control and prevention of infections by coronaviruses
WO2023039474A1 (fr) * 2021-09-08 2023-03-16 Dana-Farber Cancer Institute, Inc. Conjugués peptide-cholestérol de sars-cov-2 antiviraux structurellement insérés et leurs utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7151163B2 (en) * 2003-04-28 2006-12-19 Sequoia Pharmaceuticals, Inc. Antiviral agents for the treatment, control and prevention of infections by coronaviruses
WO2023039474A1 (fr) * 2021-09-08 2023-03-16 Dana-Farber Cancer Institute, Inc. Conjugués peptide-cholestérol de sars-cov-2 antiviraux structurellement insérés et leurs utilisations

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