Diabetes and Obesity Drug Discovery & Therapy (Track)

Designed inhibitors of insulin-degrading enzyme as promising pharmacophores for the treatment of diabetes

Malcolm A Leissring
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.

Abstract:

Enhancement of insulin signaling, a central goal for all antidiabetic therapies, can in principle be achieved by blocking the clearance of insulin by proteolytic degradation and other catabolic processes. Degradation and inactivation of insulin is mediated primarily if not exclusively by insulin-degrading enzyme (IDE), a structurally and evolutionarily distinctive zinc-metalloprotease. Despite IDE''s importance for insulin metabolism and despite its recognized potential as an attractive drug target, inhibitors of IDE have proven to be surprisingly elusive. We describe herein the design, synthesis, and enzymological and functional characterization of the first potent and selective inhibitors of IDE. Crystallographic analysis of our most potent inhibitor bound to human IDE reveals a novel mode of inhibition based on stabilization of the inactive conformation of IDE. In addition to the "insulin sparing" effects anticipated from inhibition of insulin catabolism, IDe inhibitors also show unanticipated "insulin sensitizing" effects in cells, mediated by reduced catabolism of insulin downstream of binding to the insulin receptor. Progress on the optimization of this novel class of inhibitor and their characterization in animal models will be discussed.