Silanediol protease inhibitors: From conception to validation

Silanediols are isosteric with the unstable hydrated carbonyl group, but are most commonly associated with polymerization to give silicone polymers. Placement of a silanediol in a dipeptide analogue yields a new kind of nonhydrolyzable transition-state-analogue protease inhibitor. Both metallo and aspartic protease inhibitors have been prepared using silanediols, with enzyme inhibition in the low nanomolar range. Structure-activity comparisons with known inhibitors, efficacy in whole cell assays, and a crystal structure of a sitanediol inhibitor bound to the thermolysin active site establish these silanediol inhibitors as effective and predictable new protease inhibitor tools. Recent chemistry developments have led to efficient and streamlined preparation of these inhibitors. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006).