STITCHED POLYPEPTIDES

• US 20100184645A1
• Filed: 03/28/2008
• Published: 07/22/2010
• 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.
• Granted Patent: US 8,592,377 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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:

3. The polypeptide according to claim 1, wherein all corresponds to a double bond.

5. The polypeptide according to claim 1, wherein K, L₁, L₂, and M, independently, corresponds to a cyclic or acyclic, branched or unbranched, substituted or unsubstituted C_1-20 alkylene.

6. The polypeptide according to claim 5, wherein K, L₁, L₂, and M, independently, corresponds to the formulae —

(CH₂)_g+1—

, and g is 0 to 10.

7. The polypeptide according to claim 1, wherein when L₁ is a bond, L₂ is not a bond, or when L₂ is a bond, L₁ is not a bond.

8. The polypeptide according to claim 1, wherein R^a is hydrogen.

9. The polypeptide according to claim 1, wherein R^b is hydrogen.

10. The polypeptide according to claim 1, wherein R^f is a label optionally joined by a linker.

11. The polypeptide according to claim 10, wherein R^f is a label joined by a heteroalkylene linker.

12. The polypeptide according to claim 11, wherein the heteroalkylene linker is selected from:

13. The polypeptide according to claim 11, wherein the label is selected from:

16. The method of making a substantially alpha-helical polypeptide according to claim 3, said method further comprising the steps of:

(vi) treating the polypeptide of step (v) with a catalyst.

17. The method according to claim 16, wherein said catalyst is a ruthenium catalyst.

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

4. The polypeptide according to claim 2, wherein all corresponds to a single or double bond.

14. The polypeptide according to claim 2, said polypeptide selected from polypeptides of SEQ ID 1 to SEQ ID 122.

20. A method of treating a disease, disorder, or condition in a subject, said method comprising administering a therapeutically effective amount of a substantially alpha-helical polypeptide of claim 2 to a subject in need thereof.

15. A method of making a substantially alpha-helical polypeptide, said method comprising the steps of:

(i) providing a bis-amino acid of the formula (A);

18. A bis-amino acid having the formula:

19. (canceled)