Preventing and reversing the formation of advance glycosylation endproducts

Abstract

The present invention relates to methods for inhibiting and reversing nonenzymatic cross-linking (protein aging). Accordingly, compositions are disclosed which comprise an agent capable of inhibiting the formation of advanced glycosylation endproducts of target proteins, and which additionally reverse pre-formed crosslinks in the advanced glycosylation endproducts by cleaving alpha-dicarbonyl-based protein crosslinks present in the advanced glycosylation endproducts. Certain useful agents are thiazolium salts. The method comprises contacting the target protein with the composition. Both industrial and therapeutic applications for the invention are envisioned, as food spoilage and animal protein aging can be treated. A novel immunoassay for detection of the reversal of the nonenzymatic crosslinking is also disclosed.

1 . A method for treating or ameliorating a disease in an animal, said method comprising administering to the animal an effective amount of a pharmaceutical composition, said composition comprising a compound of Formula (I), 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are methyl;
 Z is hydrogen; 
 Y is a group of the formula: 
 
       
         
           
           
               
               
           
         
       
       wherein R is phenyl; and
 X is halide, and 
 a pharmaceutically acceptable carrier therefore, 
 
       further wherein, said disease is selected from diabetes, adverse sequelae of diabetes, discoloration of teeth, kidney damage, damage to the blood vasculature, the elasticity or reducing wrinkles of the skin, hypertension, retinopathy, damage to lens proteins, peripheral neuropathy, cataracts, damage to a tissue caused by contact with elevated levels of reducing sugars, stroke, osteoarthritis, and increasing red blood cell deformability. 
     
     
         2 . The method of  claim 1 , wherein said compound is 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride. 
     
     
         3 . The method of  claim 1 , wherein said compound is 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide. 
     
     
         4 . The method of  claim 1 , wherein said disease is diabetes or adverse sequelae of diabetes. 
     
     
         5 . The method of  claim 1 , wherein said disease is the discoloration of teeth. 
     
     
         6 . The method of  claim 1 , wherein said disease is kidney damage. 
     
     
         7 . The method of  claim 1 , wherein said disease is damage to blood vasculature. 
     
     
         8 . The method of  claim 1 , wherein said disease is the elasticity or reducing wrinkles of the skin. 
     
     
         9 . The method of  claim 1 , wherein said disease is hypertension. 
     
     
         10 . The method of  claim 1 , wherein said disease is retinopathy. 
     
     
         11 . The method of  claim 1 , wherein said disease is damage to lens proteins. 
     
     
         12 . The method of  claim 1 , wherein said disease is peripheral neuropathy. 
     
     
         13 . The method of  claim 1 , wherein said disease is cataracts. 
     
     
         14 . The method of  claim 1 , wherein said disease is damage to a tissue caused by contact with elevated levels of reducing sugars. 
     
     
         15 . The method of  claim 1 , wherein said disease is stroke. 
     
     
         16 . The method of  claim 1 , wherein said disease is osteoarthritis. 
     
     
         17 . A method for increasing red blood cell deformability in an animal, said method comprising administering an effective amount of a pharmaceutical composition, said pharmaceutical composition comprising a compound of Formula (I), 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are methyl;
 Z is hydrogen; 
 Y is a group of the formula: 
 
       
         
           
           
               
               
           
         
       
       wherein R is phenyl; and
 X is halide, and 
 a pharmaceutically acceptable carrier therefor. 
 
     
     
         18 . The method of  claim 17 , wherein said compound is 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride. 
     
     
         19 . The method of  claim 18 , wherein said compound is 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide.