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J. Biol. Chem., Vol. 281, Issue 16, 11152-11160, April 21, 2006

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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 Dive¹

From the Commissariat à l'Energie Atomique, Département d'Ingénierie et d'Etudes des Protéines Bat 152, CE-Saclay, 91191 Gif/Yvette, Cedex, France and the Laboratory of Organic Chemistry, Department of Organic Chemistry, University of Athens, Panepistimiopolis, Zografou, 15771 Athens, Greece

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 10 matrix metalloproteinases (MMPs). We identified two phosphinic peptides with K_i values of 0.19 and 4.4 nM toward MMP-12 (macrophage elastase) that are more than 2-3 orders of magnitude less potent toward 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 of a nonspecific 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.

Received for publication, January 10, 2006 , and in revised form, February 13, 2006.

^* This work was supported by funds from the Commissariat à l'Energie Atomique and from the European Commission FP5RDT (QLK3-CT02-02136) and FP6RDT (Cancer Degradome project, LSHC-CT-2003-503297). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 33-1-69083585; Fax: 33-1-69089071; E-mail: vincent.dive{at}cea.fr.

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