Stitched polypeptides

• US 8,592,377 B2
• Filed: 03/28/2008
• Issued: 11/26/2013
• Est. Priority Date: 03/28/2007
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Verdine, Gregory L., Kim, Young-Woo
• Primary Examiner(s): JARRELL, NOBLE E
• Application Number:
  US12/593,384
• Publication Number:
  US 20100184645A1
• Time in Patent Office: 2,069 Days
• Field of Search: None
• US Class Current: 514/21.1
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/18 : of the parathyroid hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07C 229/30 : the carbon skeleton being acyclic and unsaturated
• CPC Class Codes: C07K 1/1075 : by covalent attachment of amino acids or peptide residues
• CPC Class Codes: C07K 1/113 : without change of the primary structure
• CPC Class Codes: C07K 14/001 : by chemical synthesis
• CPC Class Codes: C07K 14/005 : from viruses
• CPC Class Codes: C07K 14/4705 : stimulating, promoting or activating activity
• CPC Class Codes: C07K 14/4746 : p53
• CPC Class Codes: C07K 14/4747 : Apoptosis related proteins
• CPC Class Codes: C07K 14/605 : Glucagons
• CPC Class Codes: C07K 14/705 : Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 7/06 : having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 : having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: C12N 2740/16322 : New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2770/24222 : New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 7/00 : Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00
• CPC Class Codes: C12N 9/22 : Ribonucleases RNAses, DNAses catalytic nucleic acids C12N15/113
• CPC Class Codes: C12Y 301/00 : Hydrolases acting on ester bonds (3.1)

Abstract

The present invention provides inventive stitched polypeptides, pharmaceutical compositions thereof, and methods of making and using inventive stitched polypeptides.

Claims

1. A substantially alpha-helical polypeptide of the formula:

2. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1, wherein all correspond to a single or double bond.

3. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1, wherein all correspond to a single bond.

4. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1, wherein all correspond to a double bond.

5. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1, wherein R^a is hydrogen.

6. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1, wherein R^b is hydrogen.

7. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1, wherein R^f is a label optionally joined by a linker.

8. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 7, wherein R^f is a label joined by a heteroalkylene linker.

9. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 8, wherein the heteroalkylene linker is selected from the group consisting of:

10. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 8, wherein the label is selected from the group consisting of:

11. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1, that is selected from the group consisting of SEQ ID NOs:

1-122.

12. A method of making the alpha-helical polypeptide of claim 1 or its pharmaceutically acceptable salt, comprising:

coupling amino acids of formulae (A), (B), and (C);

13. The method of claim 12, wherein the catalyst is a ring closing metathesis catalyst.

14. The method of claim 12, wherein the catalyst is a ruthenium catalyst.

15. A pharmaceutical composition comprising at least one of the substantially alpha-helical polypeptide of claim 1, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

16. The substantially alpha-helical polypeptide of claim 1, or its pharmaceutically acceptable salt, wherein y is 3, and z is 3.

17. The substantially alpha-helical polypeptide of claim 1, or its pharmaceutically acceptable salt, wherein y is 3, and z is 6.

18. The alpha-helical polypeptide of claim 1, or its pharmaceutically acceptable salt, wherein y is 6, and z is 3.

19. An alpha-helical polypeptide of the formula:

20. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein R^a is hydrogen.

21. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein R^b is hydrogen or methyl.

22. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein y is 2, and z is 2, 3, 5 or 6.

23. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein y is 3, and z is 2, 3, 5 or 6.

24. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein y is 5, and z is 2, 3, 5 or 6.

25. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein y is 6, and z is 2, 3, 5 or 6.

26. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein corresponds to a double bond.

27. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein L₁ and L₂ are both CH₂CH₂CH₂.

28. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein L₁ and L₂ are both CH₂CH₂CH₂CH₂.

29. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein L₁ and L₂ are both CH₂CH₂CH₂CH₂CH₂.

30. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein L₁ and L₂ are both CH₂CH₂CH₂CH₂CH₂CH₂.

31. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein L₁ and L₂ are both CH₂CH₂CH₂CH₂CH₂CH₂CH₂.

32. The polypeptide or its pharmaceutically acceptable salt of claim 19, selected from the group consisting of SEQ ID NO:

10 to SEQ ID No;

20, SEQ ID NO;

25, SEQ ID NO;

27 to 35, SEQ ID NO;

37 to SEQ ID NO;

122, and pharmaceutically acceptable salts thereof.

33. A pharmaceutical composition comprising the polypeptide or its pharmaceutically acceptable salt of claim 19 and a pharmaceutically acceptable carrier.