Stitched polypeptides

• US 9,556,227 B2
• Filed: 09/13/2013
• Issued: 01/31/2017
• 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: Kim, Young-Woo, Verdine, Gregory L.
• Primary Examiner(s): JARRELL, NOBLE E
• Application Number:
  US14/027,064
• Publication Number:
  US 20140011979A1
• Time in Patent Office: 1,236 Days
• Field of Search: None
• US Class Current: 1/1
• 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. An amino acid having Formula (A), or a salt thereof:

2. The amino acid of claim 1, wherein R^a is alkyl.

3. The amino acid of claim 1, wherein R^a is hydrogen.

4. The amino acid of claim 1, wherein R^a is —

COCH₃.

5. The amino acid of claim 1, wherein R^f is hydrogen.

6. The amino acid of claim 1, wherein R^e is hydrogen.

7. The amino acid of claim 1, wherein R^f is an amino protecting group.

8. The amino acid of claim 7, wherein R^f is Boc.

9. The amino acid of claim 7, wherein R^f is Fmoc.

10. The amino acid of claim 1, wherein each is a double bond.

11. The amino acid of claim 1 of Formula (A-2):

12. The amino acid of claim 11 of one of the following formulae:

29. The amino acid of claim 1, wherein both correspond to a double bond.

30. The amino acid of claim 1, wherein both correspond to a triple bond.

31. The amino acid of claim 1, wherein R^c is hydrogen.

32. The amino acid of claim 1, wherein L₁ and L₂ are both —

CH₂CH₂CH₂—

, —

CH₂CH₂CH₂CH₂—

, —

CH₂CH₂CH₂CH₂CH₂—

, or —

CH₂CH₂CH₂CH₂CH₂CH₂—

.

13. A method of preparing an alphahelical polypeptide, said method comprising the steps of:

(i) providing an amino acid of Formula (A);

14. The method of claim 13, wherein said catalyst is a ring closing metathesis catalyst.

15. The method of claim 13, wherein said catalyst is a ruthenium catalyst.

16. The method of claim 13, wherein each R^a is hydrogen or methyl.

17. The method of claim 13, wherein each R^a is hydrogen.

18. The method of claim 13, wherein at least one R^a is —

COCH₃.

19. The method of claim 13, wherein each R^b is alkyl.

20. The method of claim 13, wherein each R^b is methyl.

21. The method of claim 13, wherein each R^f is hydrogen.

22. The method of claim 13, wherein each R^e is hydrogen.

23. The method of claim 13, wherein each R^f is an amino protecting group.

24. The method of claim 13, wherein each R^f is Boc.

25. The method of claim 13, wherein each R^f is Fmoc.

26. The method of claim 13, wherein each is a double bond.

27. The method of claim 13, wherein the amino acid of Formula (A) is an amino acid of Formula (A-2):

28. The method of claim 27, wherein the amino acid of Formula (A-2) is of one of the following formulae: