Development of selective inhibitors and substrate of matrix metalloproteinase-12

doi:10.1074/jbc.M600222200

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Papers In Press, published online ahead of print February 15, 2006
J. Biol. Chem, 10.1074/jbc.M600222200
Submitted on January 10, 2006
Revised on February 13, 2006
Accepted on February 15, 2006

Development of selective inhibitors and substrate of matrix metalloproteinase-12

Laurent Devel, Vassilis Rogakos, Arnaud David, Anastasios Makaritis, Fabrice Beau, Philippe Cuniasse, Athanasios Yiotakis, and Vincent Dive

Département d'Etudes et d'Ingénierie des Protéines (DIEP), CEA-Commissariat à l'Energie Atomique, Gif/Yvette, Cedex 91191

Corresponding Author: vincent.dive{at}cea.fr

Four phosphinic peptide libraries with compounds having the general formula p-Br-Ph-(PO2-CH2)-Xaa’-Yaa’-Zaa’-NH2 have been prepared and screened against ten matrix metalloproteinases (MMPs). We identified two phosphinic peptides with Ki values of 0.19 nM and 4.4 nM towards MMP-12 (macrophage elastase) that are more than 2 to 3 orders of magnitude less potent towards the other MMPs tested. These highly selective MMP-12 inhibitors contain a Glu-Glu motif in their Yaa’-Zaa’ positions. Incorporation of this Glu-Glu motif into the sequence a non-specific fluorogenic peptide cleaved by MMPs provides a highly selective substrate for MMP-12. A model of one of these inhibitors interacting with MMP-12 suggests that the selectivity observed might be due, in part, to the presence of two unique polar residues in MMP-12, Thr239 and Lys177. These MMP-12 selective inhibitors may have important therapeutic applications to diseases in which MMP-12 has been suggested to play a key role, such as in emphysema, atherosclerosis and aortic abdominal aneurysm.

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