Diabetic nephropathy, a complication of both insulin dependent (IDDM) and non-insulin dependent diabetes (NIDDM), is a significant public health problem. Advanced glycation end products (AGEs) have been correlated with the appearance and progression of diabetic renal disease. A critical step in the production of AGEs is the formation of 3-deoxyglucosone (3DG), a reactive dicarbonyl sugar. Urine and plasma levels of 3DG are two-fold higher in the diabetic population than in unaffected individuals. The non- enzymatic production of 3DG was well known, thus making this intermediate appear refractory to effective pharmacological intervention. Work in Dr. Brown's laboratory has provided significant evidence of an enzymatically mediated reaction which produces 3DG as a by-product. In this pathway, fructoselysine kinase (FLK) phosphorylates fructoselysine to produce an unstable intermediate fructoselysine 3-phosphate (FL3P). FL3P decomposes to yield lysine, inorganic phosphate and 3DG. Preliminary work shows that it is possible to inhibit FLK in vivo and thus decrease urinary output of 3DG. The enzyme involved, FLK, is a novel therapeutic target for the development of drugs to decrease 3DG production and thus AGE formation and diabetic nephropathy. This application seeks support in Phase I to develop new inhibitors of FLK by synthesizing a series of six non-metabolizable substrate analogues, testing them in vitro with a partially purified solution of FLK and, using the most efficacious structural analogue, determine the amount of inhibitor needed to reduce 3DG levels in vivo by 50% in nondiabetic rats. Phase II would provide an in vivo demonstration that reducing 3DG by this amount in diabetic rats would delay or prevent the development of kidney pathology. PROPOSED COMMERCIAL APPLICATIONS: Diabetes is the leading cause of end-stage renal disease, accounting for 35% of all new cases. From 1.6 to 2.7 million of the approximately 16 million diabetics in America will develop nephropathy requiring therapeutic treatment. Prophylactic treatment to maintain renal function could be extended to most diabetics. Since there are now no therapeutics specifically developed to treat diabetic nephropathy the market potential for a successful new treatment based on the discovery of the FLK pathway is many billions of dollars.
