The long-term objective is to design and develop potent and highly specific inhibitors of the enzyme aldose reductase. Aldose reductase catalyzes the reduction of glucose to sorbitol. It has been implicated in the pathogenesis of the chronic complications of diabetes mellitus. Current inhibitors of this enzyme lack specificity and potency, and are associated with undesirable side effects. Our experience with the structure-based design of inhibitors of purine nucleoside phosphorylase indicates that knowledge of the three demensional structure of a target enzyme, and its active site, is a tremendous aid to the development of inhibitors that are both safe and highly specific. We have solved and refined the X-ray crystal structure of porcine aldose reductase apo-enzyme, and have obtained crystals and solved the structures of both porcine and human aldose reductase complexed with its cofactor NADPH. Our goal is to locate and characterize the binding sites of the enzymatic substrate glucose and the best existing aldose reductase inhibitors in Phase I, and then to design and synthesize potent and specific inhibitors of the enzyme-based on this information in Phase II.Awardee's statement of the potential commercial applications of the research:Aldose reductase inhibitors developed from this research will be pursued as drug candidates for the treatment of diabetic complications.National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
