Methods for preventing or treating mitochondrial permeability transition

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.

1 . A method of reducing the number of mitochondria undergoing mitochondrial permeability transition (MPT), or preventing mitochondrial permeability transitioning in a mammal in need thereof, the method comprising administering to the mammal an effective amount of an aromatic-cationic peptide having:
 (a) at least one net positive charge;   (b) a minimum of four amino acids;   (c) a maximum of about twenty amino acids;   (d) 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   (e) a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p t ) wherein 2a 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.   
     
     
         2 . The method according to  claim 1 , wherein 2 p m  is the largest number that is less than or equal to r+1. 
     
     
         3 . The method according to  claim 1 , wherein a is equal to p t . 
     
     
         4 . The method according to  claim 1 , wherein the peptide has a minimum of two positive charges. 
     
     
         5 . The method according to  claim 1 , wherein the peptide has a minimum of three positive charges. 
     
     
         6 . The method according to  claim 1 , wherein the peptide is water soluble. 
     
     
         7 . The method according to  claim 1 , wherein the peptide comprises one or more D-amino acids. 
     
     
         8 . The method according to  claim 1 , wherein the C-terminal carboxyl group of the amino acid at the C-terminus is amidated. 
     
     
         9 . The method according to  claim 1 , wherein the peptide comprises one or more non-naturally occurring amino acids. 
     
     
         10 . The method according to  claim 1 , wherein the peptide has a minimum of four amino acids. 
     
     
         11 . The method according to  claim 1 , wherein the peptide has a maximum of about twelve amino acids. 
     
     
         12 . The method according to  claim 1 , wherein the peptide has a maximum of about nine amino acids. 
     
     
         13 . The method according to  claim 1 , wherein the peptide has a maximum of about six amino acids. 
     
     
         14 . The method according to  claim 1 , wherein the peptide has mu-opioid receptor agonist activity. 
     
     
         15 . The method according to  claim 1 , wherein the peptide does not have mu-opioid receptor agonist activity. 
     
     
         16 . The method according to  claim 1 , wherein the mammal is a human.