Compositions and methods for counteracting effects of reactive oxygen species and free radicals

Abstract

Peptide compounds and methods for upregulating expression of a gene encoding an antioxidative enzyme, such as superoxide dismutase or catalase, to counteract harmful oxidative effects of reactive oxygen species and other free radicals are described. The peptide compounds may be used to treat or prevent diseases and conditions characterized by undesirable elevation of reactive oxygen species and other free radicals, to upregulate AP-1 gene expression, and to treat pain. The peptide compounds may be used as components of pharmaceuticals and dietary supplements.

1 - 103 . (canceled)  
     
     
         104 . An isolated peptide compound having the formula:  
         R 1  Xaa 1  Xaa 2  Xaa 3  R 2 ,  
       wherein Xaa 1  is Asp or Glu; Xaa 2  is absent or any amino acid; Xaa 3  is Ala or Gly; R 1  is absent or is an amino terminal capping group; R 2  is absent or is a carboxy terminal capping group.  
     
     
         105 . The peptide compound according to  claim 104 , wherein R 1  is selected from the group consisting of: 
 1 to 6 lysine residues; 1 to 6 arginine residues; a glucose-3-O-glycolic acid group; an acyl group containing a hydrocarbon chain from 1 to 25 carbon atoms in length; an acetyl group; a palmitoyl group; a lipoic acid group; a docosahexaenoic acid group; and combinations thereof.    
     
     
         106 . The peptide compound according to  claim 104 , wherein R 1  is a lipoic acid group.  
     
     
         107 . The peptide compound according to  claim 104 , wherein the peptide compound is R 1  Asp Gly R 2 .  
     
     
         108 . The peptide compound according to  claim 107 , wherein R 1  is selected from the group consisting of: 
 1 to 6 lysine residues; 1 to 6 arginine residues; a glucose-3-O-glycolic acid group; an acyl group containing a hydrocarbon chain from 1 to 25 carbon atoms in length; an acetyl group; a palmitoyl group; a lipoic acid group; a docosahexaenoic acid group; and combinations thereof.    
     
     
         109 . The peptide compound according to  claim 107 , wherein R 1  is a lipoic acid group.  
     
     
         110 . The peptide compound according to  claim 104 , wherein the peptide compound is R 1  Glu Ala R 2 .  
     
     
         111 . The peptide compound according to  claim 110 , wherein R 1  is selected from the group consisting of: 
 1 to 6 lysine residues; 1 to 6 arginine residues; a glucose-3-O-glycolic acid group; an acyl group containing a hydrocarbon chain from 1 to 25 carbon atoms in length; an acetyl group; a palmitoyl group; a lipoic acid group; a docosahexaenoic acid group; and combinations thereof.    
     
     
         112 . The peptide compound according to  claim 110 , wherein R 1  is a lipoic acid group.  
     
     
         113 . The peptide compound according to  claim 104 , wherein the peptide compound is R 1  Asp Ala R 2 .  
     
     
         114 . The peptide compound according to  claim 113 , wherein R 1  is selected from the group consisting of: 
 1 to 6 lysine residues; 1 to 6 arginine residues; a glucose-3-O-glycolic acid group; an acyl group containing a hydrocarbon chain from 1 to 25 carbon atoms in length; an acetyl group; a palmitoyl group; a lipoic acid group; a docosahexaenoic acid group; and combinations thereof.    
     
     
         115 . The peptide compound according to  claim 113 , wherein R 1  is a lipoic acid group.  
     
     
         116 . The peptide compound according to  claim 104 , wherein the peptide compound is R 1  Glu Gly R 2 .  
     
     
         117 . The peptide compound according to  claim 116 , wherein R 1  is selected from the group consisting of: 
 1 to 6 lysine residues; 1 to 6 arginine residues; a glucose-3-O-glycolic acid group; an acyl group containing a hydrocarbon chain from 1 to 25 carbon atoms in length; an acetyl group; a palmitoyl group; a lipoic acid group; a docosahexaenoic acid group; and combinations thereof.    
     
     
         118 . The peptide compound according to  claim 116 , wherein R 1  is a lipoic acid group.  
     
     
         119 . The peptide compound according to  claim 104 , wherein the carboxy terminal capping group is an amino group linked to the carboxy terminal carbonyl in an amide linkage.  
     
     
         120 . The peptide compound according to  claim 119 , wherein said amino group is a primary or secondary amine.  
     
     
         121 . A pharmaceutical composition for treating or preventing a disease or condition in a human in need thereof, comprising an effective amount of a peptide compound having the formula:  
         R 1  Xaa 1  Xaa 2  Xaa 3  R 2 ,  
       wherein Xaa 1  is Asp or Glu; Xaa 2  is absent or any amino acid; Xaa 3  is Ala or Gly; R 1  is absent or is an amino terminal capping group; R 2  is absent or is a carboxy terminal capping group.  
     
     
         122 . The peptide compound according to  claim 121 , wherein R 1  is selected from the group consisting of: 
 1 to 6 lysine residues; 1 to 6 arginine residues; a glucose-3-O-glycolic acid group; an acyl group containing a hydrocarbon chain from 1 to 25 carbon atoms in length; an acetyl group; a palmitoyl group; a lipoic acid group; a docosahexaenoic acid group; and combinations thereof.    
     
     
         123 . The peptide compound according to  claim 122 , wherein R 1  is a lipoic acid group.  
     
     
         124 . The pharmaceutical composition according to  claim 121 , wherein the peptide compound is R 1  Asp Gly R 2 .  
     
     
         125 . The peptide compound according to  claim 124 , wherein R 1  is selected from the group consisting of: 
 1 to 6 lysine residues; 1 to 6 arginine residues; a glucose-3-O-glycolic acid group; an acyl group containing a hydrocarbon chain from 1 to 25 carbon atoms in length; an acetyl group; a palmitoyl group; a lipoic acid group; a docosahexaenoic acid group; and combinations thereof.    
     
     
         126 . The peptide compound according to  claim 124 , wherein R 1  is a lipoic acid group.  
     
     
         127 . The pharmaceutical composition according to  claim 121 , wherein the peptide compound is R 1  Glu Ala R 2 .  
     
     
         128 . The peptide compound according to  claim 127 , wherein R 1  is selected from the group consisting of: 
 1 to 6 lysine residues; 1 to 6 arginine residues; a glucose-3-O-glycolic acid group; an acyl group containing a hydrocarbon chain from 1 to 25 carbon atoms in length; an acetyl group; a palmitoyl group; a lipoic acid group; a docosahexaenoic acid group; and combinations thereof.    
     
     
         129 . The peptide compound according to  claim 127 , wherein R 1  is a lipoic acid group.  
     
     
         130 . The pharmaceutical composition according to  claim 121 , wherein the peptide compound is R 1  Asp Ala R 2 .  
     
     
         131 . The peptide compound according to  claim 130 , wherein R 1  is selected from the group consisting of: 
 1 to 6 lysine residues; 1 to 6 arginine residues; a glucose-3-O-glycolic acid group; an acyl group containing a hydrocarbon chain from 1 to 25 carbon atoms in length; an acetyl group; a palmitoyl group; a lipoic acid group; a docosahexaenoic acid group; and combinations thereof.    
     
     
         132 . The peptide compound according to  claim 130 , wherein R 1  is a lipoic acid group.  
     
     
         133 . The pharmaceutical composition according to  claim 121 , wherein the peptide compound is R 1  Glu Gly R 2 .  
     
     
         134 . The peptide compound according to  claim 133 , wherein R 1  is selected from the group consisting of: 
 1 to 6 lysine residues; 1 to 6 arginine residues; a glucose-3-O-glycolic acid group; an acyl group containing a hydrocarbon chain from 1 to 25 carbon atoms in length; an acetyl group; a palmitoyl group; a lipoic acid group; a docosahexaenoic acid group; and combinations thereof.    
     
     
         135 . The peptide compound according to  claim 133 , wherein R 1  is a lipoic acid group.  
     
     
         136 . The pharmaceutical composition according to  claim 121 , wherein the carboxy terminal capping group is an amino group linked to the carboxy terminal carbonyl in an amide linkage.  
     
     
         137 . The pharmaceutical composition according to  claim 121 , wherein the disease or condition is selected from the group consisting of cerebral ischemia (stroke), myocardial infarct (heart attack), renal reperfusion damage, atherosclerosis, head trauma, brain trauma, spinal cord trauma, oxygen toxicity in premature infants, premature aging, neurodegenerative diseases, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, arthritis and other inflammatory diseases or conditions, diabetes, ulcerative colitis, human leukemia and other cancers characterized by elevation of ROS or free radicals, age-related elevation of ROS or free radicals, senility, Down syndrome, macular degeneration, cataracts, schizophrenia, epilepsy, septic shock, polytraumatous shock, burn injuries, radiation-induced elevation of ROS and free radicals, and drug-induced elevation of reactive oxygen species or other free radicals.  
     
     
         138 . The pharmaceutical composition according to  claim 121 , wherein the disease or condition is cerebral ischemia.  
     
     
         139 . The pharmaceutical composition according to  claim 121 , wherein the disease or condition is myocardial infarct.  
     
     
         140 . A pharmaceutical composition for treating or preventing ischemia in a human in need thereof, comprising an effective amount of a peptide compound having 2 to 7 amino acids.  
     
     
         141 . The pharmaceutical composition of  claim 140 , wherein the peptide compound further comprises an amino terminal capping group or a carboxy terminal capping group.  
     
     
         142 . The pharmaceutical composition of  claim 141 , wherein the amino terminal capping group is a lipoic acid group.