Preventing and reversing the formation of advance glycosylation endproducts

Abstract

The present invention relates to compositions and 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 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.  
 
   
   
       2 . A compound according to  claim 1 , wherein said compound is 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride.  
   
   
       3 . A method for treating diabetes or treating or ameliorating adverse sequelae of diabetes in an animal, said method comprising administering to the animal a diabetes treating or adverse sequelae of diabetes treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       4 . A method of treating or ameliorating the discoloration of teeth, said method comprising administering a teeth discoloration inhibiting effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       5 . A method for treating or ameliorating kidney damage in an animal, said method comprising administering a kidney treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       6 . A method for treating or ameliorating damage to blood vasculature in an animal, said method comprising administering a blood vasculature damage treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       7 . A method for treating or ameliorating the elasticity or reducing wrinkles of the skin of an animal, said method comprising administering a skin elasticity or wrinkle reducing effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       8 . A method for treating or ameliorating hypertension in an animal, said method comprising administering a hypertension treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       9 . A method for treating or ameliorating retinopathy in an animal, said method comprising administering a retinopathy treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       10 . A method for treating or ameliorating damage to lens proteins in an animal, said method comprising administering a lens damage treating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       11 . A method for treating or ameliorating peripheral neuropathy in an animal, said method comprising administering a peripheral neuropathy treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       12 . A method for treating or ameliorating cataracts in an animal, said method comprising administering a cataract treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       13 . A method for treating or ameliorating damage to a tissue caused by contact with elevated levels of reducing sugars in an animal, said method comprising administering a peripheral neuropathy treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       14 . A method for treating or ameliorating stroke in an animal, said method comprising administering a stroke treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       15 . A method for treating or ameliorating osteoarthritis in an animal, said method comprising administering an osteoarthritis treating or ameliorating effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.  
   
   
       16 . A method for increasing red blood cell deformability in an animal, said method comprising administering a red blood cell deformability increasing effective amount of a pharmaceutical composition, said pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier therefor.