[go: up one dir, main page]

WO1993024518A1 - Conception et synthese d'une substance mimetique a virage beta de cd4 inhibant la liaison gp120 du vih - Google Patents

Conception et synthese d'une substance mimetique a virage beta de cd4 inhibant la liaison gp120 du vih Download PDF

Info

Publication number
WO1993024518A1
WO1993024518A1 PCT/US1993/005084 US9305084W WO9324518A1 WO 1993024518 A1 WO1993024518 A1 WO 1993024518A1 US 9305084 W US9305084 W US 9305084W WO 9324518 A1 WO9324518 A1 WO 9324518A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino acid
beta
side chain
natural
mimetics
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.)
Ceased
Application number
PCT/US1993/005084
Other languages
English (en)
Inventor
Michael Kahn
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.)
University of Illinois at Urbana Champaign
University of Illinois System
Original Assignee
University of Illinois at Urbana Champaign
University of Illinois System
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 University of Illinois at Urbana Champaign, University of Illinois System filed Critical University of Illinois at Urbana Champaign
Publication of WO1993024518A1 publication Critical patent/WO1993024518A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70514—CD4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid

Definitions

  • the invention relates to the development of therapeutic agents for inhibiting HIV-1.
  • T cell surface glycoprotein CD4 acts as the cellular receptor for human immunodeficiency virus type 1 through recognition of the virus envelope glycoprotein gpl20.
  • the development of agents that can inhibit CD4-gpl20 interaction is a critical goal in the field of therapeutic approaches to AIDS treatment. Fisher et al., Nature 221: 76-78 (1988) teaches that recombinant soluble proteins.
  • CD4 is an inhibitor of both virus replication and syncytium formation.
  • CD4 amino acids 37-53 comprise a binding site for the AIDS virus.
  • the invention further relates to peptide mimetics, which are chemical structures which serve as appropriate substitutes for peptides in interactions with receptors and enzymes. More particularly, the invention relates to the use of peptide mimetics to inhibit viral protein-receptor interactions necessary for viral infection.
  • peptide mimetics can be defined as structures which serve as appropriate substitutes for peptides in interactions with receptors and enzymes.
  • the development of rational approaches for discovering peptide mimetics is a major goal of medicinal chemistry. Such development has been attempted both by empirical screening approaches and by specific synthetic design.
  • Monocyclic lactams have generally been useful as external beta-turn mimetics for studying receptor-peptide interactions.
  • the mimetic skeleton in these molecules is external to the beta-turn, which gives rise to numerous limitations. Chief among these is bulkiness, which requires the use of dipeptide mimetics, rather than mimetics of all four residues in an actual beta-turn. Substantial flexibility retained in these beta-turn mimetics makes it unsafe to assume that expected conformations are present, absent considerable conformational analysis.
  • Vallee et al. Int. J. Pept. Prot. Res. 22: 181-190 (1989) discloses that a monocyclic lactam beta-turn mimetic did not contain an expected type II' beta-turn in its crystal structure.
  • the limitations presented by external beta-turn mimetics may be minimized by using mimetics in which the mimetic skeleton approximately replaces the space that was occupied by the peptide backbone in the natural beta-turn. Such molecules are known as internal beta-turn mimetics. Internal beta-turn mimetics may not generally reproduce the geometry of the peptide backbone of the particular beta- turn as accurately as external beta-turn mimetics. However, the internal position of the constraint allows replacement of larger sections of peptide, thus making tetrapeptide mimetics possible. The lack of bulk also diminishes the likelihood of steric hindrance of binding by the mimetic skeleton.
  • beta-turn mimetics having biological activity are known in the art.
  • Krstenansky et al. Biochem. Biophys. Commun. 102: 1368-1374 (1982) discloses a leucine enkephalin analog in which an internal beta-turn mimetic replaced the residues Gly ⁇ -Gly ⁇ -Phe ⁇ -Leu ⁇ , and which acted as an analgesic with one-third the potency of morphine.
  • Other internal beta-turn mimetics have been described.
  • Kahn et al. Tetrahedron Lett. 2£: 1623-1626 (1987), discloses a type I beta-turn mimetic which can be incorporated into a peptide via its amino and carboxy termini, and which is designed to mimic an idealized type I beta-turn. See also Kahn et al., J. Am. Chem. Soc. JJD: 1638-1639 (1988); Kahn et al., J. Mol. Recogn. 1: 75-79 (1988).
  • CD4 is a glycoprotein found on the surface of T lymphocytes; during HIV infection in humans, CD4 is the receptor for the gp 120 envelope glycoprotein of HIV.
  • Extensive mutagenesis and peptide mapping experiments have mapped a critical binding region of CD4 to a single stretch of amino acids. Recent X-ray analysis has shown that within this stretch, residues 40-45 exhibit a beta-turn conformation. In addition, residues 83- 92 apparently are involved in syncytium formation.
  • the invention provides a novel approach to synthesize conformationally restricted peptidomimetics of chain reversals in peptides and proteins.
  • the invention provides a method for the design and synthesis of a mimetic of residues Gin ⁇ O-Thr ⁇ which form a m between the C and C" beta-strands of CD4.
  • the method further provides a mimetic that inhibits binding of soluble gpl20 to cells expressing CD4 at moicromolar concentrations and reduces syncytium formation, and will provide a foundation for the development of low molecular weight gpl20 binding inhibitors as therapeutic agents.
  • FIG. 1 Basic structure of mimetic ring system for residues 40-45 of
  • FIG. 2 Full CD4 loop region mimetic structure a (peptidomimetic 1).
  • FIG. 3 Synthetic scheme described in Example 1.
  • FIG. 4 Ten membered and twelve mimetic rings corresponding to the Val86_Gin89 region of CD4 that is implicated in syncytium formation.
  • FIG. 5 Retro-Synthetic scheme for the mimetics shown in Figure 4.
  • FIG. 6 Synthetic pathway for component 4 of the retro-synthetic scheme shown in Figure 5.
  • FIG. 7 Synthetic pathway for component 6 of the retro-synthetic scheme shown in Figure 5.
  • FIG. 8 Synthetic pathway for component 7of the retro-synthetic scheme shown in Figure 5.
  • FIG. 9 Inhibition of syncytium formation by mimetic 1 (asterisks), soluble CD4 (squares), or CD4 hexapeptide of residues 40-45 (crosses).
  • FIG. 10 Data showing inhibition of gpl20 binding by soluble CD4 or by peptidomimetics of the invention.
  • FIG. 11 A peptidomimetic having both CDR2-like and CDR3-like domains.
  • the invention provides a peptide mimetic (or peptidomimetic) capable of inhibiting CD4 binding to gpl20.
  • Infection of human mononuclear cells by human immunodeficiency virus (HIV) requires the binding of the viral envelope glycoprotein gpl20 to CD4, a cell surface glycoprotein that is found principally on the helper class of T-lymphocytes.
  • HIV human immunodeficiency virus
  • CD4 a cell surface glycoprotein that is found principally on the helper class of T-lymphocytes.
  • a substance that could mimic CD4 in its ability to bind gpl20 could potentially provide a valuable therapeutic.
  • Amino acids within the CDR2-like region of CD4 have been shown to be involved in gpl20 binding.
  • This region occupies a very prominent surface exposed site in the CD4 structure.
  • the hairpin loop at Gin40.p e43 j s highly accessible.
  • the basic structure of the mimetic ring system having inhibitory effect on gpl20 binding is shown in Figure 1.
  • R ⁇ is CH2OH, CH3, CH2CH2CONH2 or a side chain of a synthetic or natural alpha amino acid and preferably CH3,
  • R2 is a side chain of a natural or synthetic alpha amino acid or H
  • R3 is CH2OH a side chain of a natural or synthetic alpha amino acid, or a lower alkyl chain having 1 to 6 carbon atoms
  • R4 is C ⁇ CgHg, a natural or synthetic amino acid side chain, 1-naphthyl- alanine, or 2-naphthyl-alanine
  • R5 is one or more natural or synthetic amino acids, hydrogen, or an acetyl or benzoyl group
  • R is an ether, amine, or one or more natural or synthetic amino acids, or a hydroxyl group.
  • the full CD4 loop region mimetic structure (Mimetic 1) is shown in Figure 2, where Bn represents benzyl.
  • Mimetics according to the invention inhibit gpl20 binding in a concentration dependent manner, with an IC50 in the micromolar range or better, as shown in Figure 10.
  • the invention further provides peptide mimetics of the CDR3-like region, which is implicated in syncytium formation.
  • a ten membered and twelve membered mimetic of this region is shown in Figure 4.
  • the invention provides peptide mimetics of a beta-turn at the tip of the CDR3-like domain, comprising the residues Val ⁇ , Glu ⁇ , As ⁇ S and Gln89.
  • Mimetics of this region may act as viricidal agents by causing premature exposure of the gp41 fiisogenic domain to cellular proteases, thus interfering with the CD4 induced release of gpl20 from virus and infected cells and interfering with syncytial formation.
  • the mimetic structure exactly or closely duplicates the structure of the natural CDR3-like region 86-89. Mimetics according to this embodiment can promote gpl20 shedding prematurely, thereby making it unproductive.
  • SUBSTITUTE SHEET constituents of the mimetics according to this embodiment of which Figure 4 is an example are: X is NH or
  • R ⁇ is an alpha amino acid side chain preferably valine;
  • R2 is a glutamate or aspartate side chain (CH2CO2H or CH2CH2CO2H);
  • R3 is an aspartate or glutamate side chain;
  • R4 is a side chain of glutamine (CH2CH2CONH2), asparagine (CH2CONH2), aspartate, or glutamate;
  • R- is acetyl, benzoyl, H, or a natural or synthetic amino acid, and
  • R is an ether, OH, an amine, or a natural or synthetic amino acid.
  • the invention provides peptide mimetics having even greater ability to inhibit binding between CD4 and gpl20.
  • peptide mimetics described in the first aspect of the invention contain structures that mimic residues Gin 40-Thr 45 of the CDR2-like region of CD4. Such peptide mimetics have about 400 nM Kj) for gpl20, abrogate binding of gpl20 to CD4+ cells at low micromolar levels, and reduce syncytium formation. However, these properties can be further improved by altering the side chains of one or more of the structures mimicking residues Gln ⁇ O-Thr ⁇ .
  • the peptide mimetics according to the first aspect of the invention have side chains corresponding to those found in the natural peptide, a,., Gln-Gly-Ser-Phe-Leu-Thr.
  • Peptide mimetics according to the second aspect of the invention have one or more modified side chain. The modifications result in superior inhibitory properties.
  • the invention provides peptidomimetics incorporating both CDR2-like and CDR3-like domains.
  • the two domains are linked in a fashion that closely mimics their spatial relationship in CD4.
  • the distance in the native molecule from the amino terminus of Asn 39 to the amino terminus of Glu 85 is only about 9.2 angstroms.
  • the two loops of CD4 are positioned in the native molecule and
  • SUBSTITUTE SHEET are positioned by beta sheet. This region can be replaced by naphthalene biscarboxylic acid, which separates the amino termini of residues 39 and 85 by 9.4 angstroms.
  • a preferred embodiment of peptidomimetics according to this aspect of the invention is shown in Figure 11. In this embodiment, R is most preferably either hydrogen or a methyl group.
  • R is most preferably either hydrogen or a methyl group.
  • Such coupling is achieved by reacting a naphthalene biscarboxylic half acid benzylester with a protected CDR3- like mimetic, followed by hydrogenolytic deprotection and coupling to the CDR2- like loop and acidic removal of the t-butyl esters.
  • the invention provides a novel method to synthesize conformationally restricted peptidomimetics of chain reversals in peptides and proteins.
  • the method of the invention provides predictable variation of side chain orientation, backbone conformations and distances.
  • the method of the invention allows the design and synthesis of a peptidomimetic of residues Gln40-Th ⁇ 45 in the C'C" CDR2-like loop of CD4, which incorporates a conformationally restricted type II beta-turn mimetic. At micromolar concentration, this peptidomimetic abrogates binding of soluble gpl20 to cells expressing CD4 on their surface.
  • An example of the method is shown in Figure 3. Synthesis of peptide mimetics corresponding to the Val ⁇ -Gln ⁇ region is illustrated in Figure 5 and described in more detail in Example 3.
  • the invention provides pharmaceutical formulations suitable for use in the treatment of AIDS.
  • Such pharmaceutical formulations comprise the gpl20-binding inhibitory peptide mimetics of the invention in a physiologically acceptable carrier or diluent.
  • SUBSTITUTE SHEET temperature slowly and the mixture was allowed to stir for about 12 hours at room temperature.
  • the mixture was washed with aqueous ammonium chloride, saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo.
  • the residue was dissolved in 50 milliliters of diethyl ether.
  • the solution was cooled to 0°C and 2.0 molar t-butylmagnesium chloride in diethyl ether (5.24 milliliters, 10.5 millimoles) was added dropwise.
  • the mixture was allowed to warm to room temperature for about 12 hours with stirring and was cooled to 0°C again. Saturated ammonium chloride was added and the mixture was stirred for 30 minutes.
  • a solution of lithium diisopropyl amide (2.5 millimoles in 25 milliliters of THF) was prepared and cooled to -78 °C.
  • the azetidinone acid (d) (238 mg, 0.59 mmol) was dissolved in 30 ml THF and cooled to 0°C. To this solution was added NMM (147 ⁇ l, 2.25 equiv.) and iBuOCOCl (81 ⁇ l, 1.05 equiv.). The solution was stirred for 15 minutes at room temperature and then added to a solution of O-benzylserine benzylester (e) in 10 ml THF (with 1 equiv. NMM) at 0°C. The reaction was allowed to warm to room temperature and stirred for 12 hours.
  • the carboxylic acid potassium salt (h) (38 mg, 0.05 mmol) was dissolved in 400 pi 1 1:1 THF:H 2 0. To this was added EDC (11 mg, 1.1 equiv.), HOBT (7.5 mg, 1.1 equiv.) and the protected dipeptide (i) (45 mg, 0.1 mmol) and the reaction was stirred at room temperature for 24 hours. Removal of the volatiles in vacuo and silica gel chromatography (50:1 CH2Cl2:MeOH) afforded 62% yield of the protected analog. A solution of this compound in 2 ml MeOH with 1 ml MeOH saturated with HC1 and 10 mg 10% Pd/C was placed under 1 atm H2 and stirred at room temperature for 16 hours. Filtration through celite and removal of the volatiles in vacuo afforded 22 mg gpl20 binding inhibitor (60% yield) (k).
  • fluoresceinated gpl20 was incubated with the mimetics or with soluble CD4 at 22 °C in binding buffer (Ca 2 + , Mg2+ free HBSS, 0.5% BSA, 0.05% sodium azide, pH 7.4). Approximately 300,000 cells (from a 10x10 ⁇ cell/ml stock) were added to tubes at 4°C in binding buffer, with a final volume of 100 microliters. Samples were incubated at 4°C for 40 min. washed in binding buffer and analyzed in FACS immediately. Data was acquired, gating on live cell population (always greater than 90%), and was consistent whether mimetics, gpl20 or other agents were added or not. Results are shown in Figure 10. Inhibition by Mimetic 1 was concentration dependent, with an IC50 of 0.8 micromolar.
  • Example 1 SUBSTITUTE SHEET described in Example 1.
  • the azetidinone component shown as (3) in Figure 5, is synthesized by Arndt-Eistart homologation of L-Valine and subsequent ring closure, as described in Buehffler et al., Helv. Chim. Acta £Q: 2747-2755 (1977).
  • Component (4) also shown in Figure 5, is synthesized by Evans' oxazolidone methodology. This synthetic pathway is shown in Figure 6. Synthesis of component 6 (in Figure 5) is accomplished by direct amination of glutamine with the oxaziridine shown in Figure 7 and described in Vidal et al., J. Chem. Soc, Chem. Commun. 435-436 (1991).
  • Preparation of component 7 is accomplished via reductive amination as shown in Figure 8 and described in Gribble and Nutaitis, Org. Prep. & Proc. Int. 12: 317-384 (1985).
  • the completed mimetics are tested for activity by assessing their ability to affect syncytial formation, as described in Example 4. Inactivity due to the absence of residues beyond the Glu85-Gln89 turn region can be remedied by addition of amino acid residues to the N terminus, C terminus or both.
  • EXAMPLE 4 Inhibition of Svncvtium Formation Sup Tl cells (see Weiner et al., Pathobiology 4: 1-20 (1991)) were used as target cells for infection. Dilutions (1:2) of soluble CD4, CD4 mimetic, or CD4 peptide were made in 96 well plates in RPMI 1640 media containing 10% fetal calf serum. H9/IIIB infected cells were then plated at a density of approximately 10 ⁇ cells per well. Sup Tl target cells were then added (5 x 10 ⁇ per well) and syncytium formation was qualitatively and quantitatively determined after a 3 day incubation period.
  • Increased effectiveness of inhibition of binding between gpl20 and CD4 and of syncytium formation can be achieved by introducing modified amino acid side chains into the mimetic. For example, substitution of the Ser42 side chain of mimetic 1 by a Leu side chain increased the inhibitory effect of the mimetic. Other
  • SUBSTITUTE SHEET side chain modifications that can increase the inhibitory effect of mimetic 1 are substitution of the Phe 43 side chain by Trp or by 1 or 2 napthylalanine, substitution of the Gly 4 * side chain by Phe,Leu, or Ala, or changing Leu 44 to HomoArg to result in the following structure:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Cell Biology (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

On décrit des composés et des procédés de synthèse de nouvelles substances mimétiques à virage bêta, ainsi que les nouvelles substances mimétiques à virage bêta elles-mêmes, et des peptides les contenant. L'invention permet de produire spécifiquement des substances mimétiques à virage bêta qui inhibent la liaison du gp 120 du CIH sur les résidus d'acides aminés 40-45 des CD4 humains, ainsi que des substances mimétiques de la région similaire à CDR3 impliquée dans la formation syncytiale.
PCT/US1993/005084 1992-05-28 1993-05-28 Conception et synthese d'une substance mimetique a virage beta de cd4 inhibant la liaison gp120 du vih Ceased WO1993024518A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US88980892A 1992-05-28 1992-05-28
US07/889,808 1992-05-28

Publications (1)

Publication Number Publication Date
WO1993024518A1 true WO1993024518A1 (fr) 1993-12-09

Family

ID=25395834

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/005084 Ceased WO1993024518A1 (fr) 1992-05-28 1993-05-28 Conception et synthese d'une substance mimetique a virage beta de cd4 inhibant la liaison gp120 du vih

Country Status (2)

Country Link
AU (1) AU4396693A (fr)
WO (1) WO1993024518A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001009191A1 (fr) * 1999-08-02 2001-02-08 Synt:Em S.A. Methodes de conception par ordinateur destinees a la production de mimetiques moleculaires
US7345020B2 (en) * 1995-06-29 2008-03-18 Thomas Jefferson University Mimetics of CD4 that inhibit immune response

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990013562A1 (fr) * 1989-05-02 1990-11-15 Genelabs Incorporated Fragments de peptides de cd4 modifies chimiquement presentant des proprietes anti-retrovirales
WO1992020704A1 (fr) * 1991-05-21 1992-11-26 Board Of Trustees Of The University Of Illinois Inhibiteurs peptidomimetiques de la liaison du gp 120 du vih au cd4

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990013562A1 (fr) * 1989-05-02 1990-11-15 Genelabs Incorporated Fragments de peptides de cd4 modifies chimiquement presentant des proprietes anti-retrovirales
WO1992020704A1 (fr) * 1991-05-21 1992-11-26 Board Of Trustees Of The University Of Illinois Inhibiteurs peptidomimetiques de la liaison du gp 120 du vih au cd4

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA. vol. 89, no. 13, 1 July 1992, WASHINGTON US pages 5872 - 5876 S. CHEN ET AL. 'Design and synthesis of a CD4 beta-turn mimetic that inhibits human immunodeficiency virus envelope glycoprotein gp120 binding and infection of human lymphocytes' *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7345020B2 (en) * 1995-06-29 2008-03-18 Thomas Jefferson University Mimetics of CD4 that inhibit immune response
WO2001009191A1 (fr) * 1999-08-02 2001-02-08 Synt:Em S.A. Methodes de conception par ordinateur destinees a la production de mimetiques moleculaires

Also Published As

Publication number Publication date
AU4396693A (en) 1993-12-30

Similar Documents

Publication Publication Date Title
US10913769B2 (en) Synthetic peptide amides and dimers thereof
US5475085A (en) Conformationally restricted mimetics of beta turns and beta bulges and peptides containing the same
CA2410662C (fr) Nouveau peptide sous forme d'inhibiteurs de protease a serine ns3 d'hepatite virale c
CA2667155C (fr) Amides peptidiques synthetiques
EP0502926B1 (fr) Peptides anti-thrombose et pseudopeptides
US5317014A (en) Peptides and pseudopeptides derived from tachykinin
AU679460B2 (en) Conformationally restricted mimetics of reverse turns and peptides containing the same
TWI423987B (zh) 環肽ｃｘｃｒ４拮抗劑
JP3248584B2 (ja) フィブロネクチン接着抑制剤
US20110212882A1 (en) Uses of kappa opioid synthetic peptide amides
CA2473032A1 (fr) Nouveaux peptides utiles comme inhibiteurs de serine protease ns3 du virus de l'hepatite c
AU2014233675A1 (en) Macrocyclic inhibitors of the PD-1/PD-L1 and CD80(B7-1)/PD-L1 protein/protein interactions
US5811400A (en) Peptide derivatives with δ opioid receptor antagonist or mixed μ agδ antagonist effects
US3856770A (en) Psychopharmacologically active tetra-, penta-, hexa-, and heptapeptides
JPH02172961A (ja) 新規なペプチダーゼ基質類似体
WO1993024518A1 (fr) Conception et synthese d'une substance mimetique a virage beta de cd4 inhibant la liaison gp120 du vih
JPH069628A (ja) ヒドロキシエチレン等量型のジチオラニルグリシン−含有ｈｉｖプロテアーゼインヒビター
KR0139535B1 (ko) 신규 펩티다제 억제제
WO1992020704A1 (fr) Inhibiteurs peptidomimetiques de la liaison du gp 120 du vih au cd4
US5610142A (en) Bradykinin antagonist pseudopeptide derivatives of substituted 4-keto-1,3,8-triazaspiro[4.5]decan-3-alkanoic acids
Altherr et al. The'azirine/oxazolone method'in peptaibol synthesis: preparation of a derivative of trichotoxin A-50 (G).
Biagini et al. Analogue and Conformational Studies on Peptides, Hormones and Other Biologically
Ramurthy Design and synthesis of CD4 peptidomimetics that inhibit HIV-gp120 binding
Gardner Design and synthesis of (beta)-turn mimetics of leucine enkephalin
JPS63239255A (ja) 新規なペプチダーゼ阻害剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP KR

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA