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Microreview
Silanediol Protease Inhibitors: From Conception to Validation†
Article first published online: 25 OCT 2005
DOI: 10.1002/ejoc.200500508
Copyright © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Additional Information
How to Cite
Sieburth, S. McN. and Chen, C.-A. (2006), Silanediol Protease Inhibitors: From Conception to Validation. Eur. J. Org. Chem., 2006: 311–322. doi: 10.1002/ejoc.200500508
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Publication History
- Issue published online: 2 JAN 2006
- Article first published online: 25 OCT 2005
- Manuscript Received: 8 JUL 2005
- Abstract
- Article
- References
- Cited By
Keywords:
- Drug design;
- Hydrolases;
- Inhibitors;
- Peptidomimetics;
- Proteases;
- Silanes;
- Silicon
Abstract
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 silanediol 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. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)