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Silanediol Protease Inhibitors: From Conception to Validation
Author(s) -
Sieburth Scott McN.,
Chen ChienAn
Publication year - 2006
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200500508
Subject(s) - chemistry , thermolysin , protease , protease inhibitor (pharmacology) , stereochemistry , enzyme , active site , dipeptide , peptidomimetic , enzyme inhibitor , combinatorial chemistry , biochemistry , virus , peptide , trypsin , virology , antiretroviral therapy , viral load , biology
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)