The present invention relates generally to the uncoupling of sugar-mediated coupling of proteins, lipids, nucleic acids, and other biomaterials, and any combination thereof, resulting from their reaction with glucose and other reducing sugars. The reaction between glucose and protein amino groups was studied in detail by Maillard in 1912, who observed that glucose or other reducing sugars react with amino acids to form adducts that undergo a series of dehydrations and rearrangements to form stable brown pigments. Further studies have suggested that stored and heat treated foods undergo nonenzymatic browning as a result of the reaction between glucose and the polypeptide chain, and that the proteins are resultantly cross-linked and correspondingly exhibit decreased bioavailability. U.S. Pat. No. 6,007,865 discloses that these reactions occur in vivo at normal glucose levels. U.S. Pat. No. 6,007,865 further terms these reactions as advanced glycosylation (or glycation) end products (AGEs).
Several therapeutic approaches have been attempted based upon intervening in the accumulation of AGEs in vivo. One approach, exemplified in U.S. Pat. No. 4,758,583, concerns the inhibition of the formation of AGEs from their precursors, by the administration of agents such as aminoguanidine and related compounds. By reacting with an early glycosylation product that results from the original reaction between the target protein and glucose, this patent discloses that these agents block the formation of AGEs and further formation of AGEs and cross-links in tissues is inhibited.
U.S. Pat. Nos. 5,656,261, 5,853,703, 6,007,865, and 6,121,300, and in P.C.T. Intl. Appl. WO97/42175, disclose agents and methods that reverse (also termed cleave or break) existing AGE cross-links in vitro and in vivo. Specifically, these patents disclose a mechanism of protein crosslinking by sugars, involving formation of a 6-hydroxy-2,3-hexanedione protein—protein cross-linking structure which has an epsilon amino group of one protein attached to the 1 position, and a nucleophilic side chain of another protein attached to the 5 position. Further, these patents disclosed compounds such as 4,5-dimethyl-3-(2-oxo-2-phenylethyl)thiazolium bromide, which were claimed to have broken protein—protein cross-links in a manner consistent with a mechanism involving transient formation of a carbanion by deprotonation of the unsubstituted 2-position of the thiazolium ring, followed by attack of the carbanion at one of the ketone carbonyls of the hypothetical 6-hydroxy-2,3-hexanedione protein—protein cross-linking structure. Subsequent rearrangements known for such thiazolium adducts could lead to cleavage of the bond between the carbonyl carbons, resulting in formation of an aldehyde fragment and a carboxylic acid fragment.
USPTO Backgrounds
USPTO Backgrounds