Poster Presentation 9th General Meeting of the International Proteolysis Society 2015

Determinant role of the zinc-binding group in the potency and selectivity of synthetic Inhibitors of MMPs (#112)

Vincent Dive 1 , C Rouanet-Mehouas 1 , B Czarny 1 , E Cassar-Lajeunesse 1 , L Devel 1 , E Stura 1
  1. CEA, Gif/Yvette, France

After the ACE inhibitor success story in the 80 years, the privileged approach to develop inhibitors of zinc-metalloproteases was based on the use of a peptidic moiety to which was grafted in the right position a zinc-chelating group. Thus, thiol, carboxylate and hydroxamic groups have been extensively used leading in most case to potent inhibitors. Our group has spent many efforts to use another zinc-binding, a phosphoryl group (PO2-), leading to phosphinic pseudo-peptides as a new family of potent and specific inhibitors of zinc-metalloproteases (1-7).
Interestingly, the role of the “zinc-binding” group on the potency and selectivity of synthetic inhibitors was up to now never reported. This has led us to prepare 3 inhibitors of MMPs, comprising the same peptidic moiety, but with 3 different zinc-binding groups: hydroxamate, carboxylate and phosphoryl (scheme 1). Potency and selectivity profiles of these inhibitors towards different MMPs revealed the influence of the zinc-binding group on these parameters. X-ray crystal structures of these inhibitors in complex with MMP-12, combined to thermodynamic studies, provided insights on the complex role played by the zinc-binding group. Carboxylate and phosphinic inhibitors provided the most selective compounds towards MMPs, while hydroxamate inhibitors displayed poor selectivity.

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