Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10804325 | Biochimie | 2010 | 8 Pages |
Abstract
Following the disappointment of clinical trials with early broad-spectrum synthetic inhibitors of matrix metalloproteases (MMPs), the field is now resurging with a new focus on the development of more selective inhibitors. Compounds able to fully discriminate between different members of the MMP family are sorely needed for therapeutic applications. Chemical efforts over the past years have led to very few selective inhibitors of MMPs. The over-exploitation of the hydroxamate function, or other strong zinc-binding groups, might be responsible for this failure. By resorting to weaker zinc-chelating groups, like phosphoryl or carboxylic groups, inhibitors with improved selectivity profiles have been developed. However, the most encouraging results have been obtained with compounds that avoid targeting the zinc but gain their affinity from plunging deeper into the MMP S1â² cavity. Analyses of the crystal structures of MMP-13 and MMP-8 complexes with such compounds provide novel insights for the design of more selective inhibitors for other members of the MMP family.
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Authors
Laurent Devel, Bertrand Czarny, Fabrice Beau, Dimitris Georgiadis, Enrico Stura, Vincent Dive,