Methods for preventing or treating mitochondrial permeability transition

• US 8,404,646 B2
• Filed: 09/28/2011
• Issued: 03/26/2013
• Est. Priority Date: 02/04/2003
• Status: Active Grant

• Current Assignee: Cornell Research Foundation Incorporated (Cornell University), Institut De Recherches Cliniques De Montreal, Lumenir, Inc.
• Original Assignee: Cornell Research Foundation Incorporated (Cornell University), Institut De Recherches Cliniques De Montreal
• Inventors: Schiller, Peter W., Szeto, Hazel H., Zhao, Kesheng
• Primary Examiner(s): Gupta, Anish
• Application Number:
  US13/247,648
• Publication Number:
  US 20120021970A1
• Time in Patent Office: 545 Days
• Field of Search: None
• US Class Current: 514/21.3
• CPC Class Codes: A61K 38/03 Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• 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: C07K 5/1008 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/1016 : and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/1019 : with the first amino acid being basic
• CPC Class Codes: C07K 5/1024 : with the first amino acid being heterocyclic

Abstract

The invention provides a method of reducing or preventing mitochondrial permeability transitioning. The method comprises administering an effective amount of an aromatic-cationic peptide having at least one net positive charge; a minimum of four amino acids; a maximum of about twenty amino acids; a relationship between the minimum number of net positive charges (p_m) and the total number of amino acid residues (r) wherein 3p_m is the largest number that is less than or equal to r+1; and a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p_t) wherein 2 a is the largest number that is less than or equal to p_t+1, except that when a is 1, p_t may also be 1.

Claims

1. A method for treating or preventing cytosolic Ca²⁺ overload caused by hypoglycemia in a mammal in need thereof, the method comprising administering to the mammal an effective amount of an aromatic-cationic peptide having the amino acid sequence

2. The method of claim 1, wherein the mammal is a human.

3. The method of claim 1, wherein the peptide is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intramuscularly, intrathecally, or transdermally.

4. The method of claim 1, wherein the peptide is combined with a pharmaceutically acceptable carrier prior to administration to the mammal.

5. The method of claim 1, wherein the peptide has the amino acid sequence D-Arg-2′

6′

Dmt-Lys-Phe-NH₂.

6. The method of claim 1, wherein the peptide has the amino acid sequence 2′

6′

Dmt-D-Arg-Phe-Lys-NH₂.

7. The method of claim 1, wherein the peptide has the amino acid sequence Phe-D-Arg-Phe-Lys-NH₂.

8. A method for preventing Ca²⁺-induced necrotic cell death caused by hypoglycemia in a mammal in need thereof, the method comprising administering to the mammal an effective amount of an aromatic-cationic peptide having the amino acid sequence

9. The method of claim 8, wherein the mammal is a human.

10. The method of claim 8, wherein the peptide is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intramuscularly, intrathecally, or transdermally.

11. The method of claim 8, wherein the peptide is combined with a pharmaceutically acceptable carrier prior to administration to the mammal.

12. The method of claim 8, wherein the peptide has the amino acid sequence D-Arg-2′

6′

Dmt-Lys-Phe-NH₂.

13. The method of claim 8, wherein the peptide has the amino acid sequence 2′

6′

Dmt-D-Arg-Phe-Lys-NH₂.

14. The method of claim 8, wherein the peptide has the amino acid sequence Phe-D-Arg-Phe-Lys-NH₂.

15. A method of regulating cytosolic Ca²⁺ levels in hypoglycemia in a mammal in need thereof, the method comprising administering to the mammal an effective amount of an aromatic-cationic peptide having the amino acid sequence

16. The method of claim 15, wherein the mammal is a human.

17. The method of claim 15, wherein the peptide is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intramuscularly, intrathecally, or transdermally.

18. The method of claim 15, wherein the peptide is combined with a pharmaceutically acceptable carrier prior to administration to the mammal.

19. The method of claim 15, wherein the peptide has the amino acid sequence D-Arg-2′

6′

Dmt-Lys-Phe-NH₂.

20. The method of claim 15, wherein the peptide has the amino acid sequence 2′

6′

Dmt-D-Arg-Phe-Lys-NH₂.

21. The method of claim 15, wherein the peptide has the amino acid sequence Phe-D-Arg-Phe-Lys-NH₂.