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J Biol Chem. 2006 Apr 21;281(16):11152-60. Epub 2006 Feb 15.

Development of selective inhibitors and substrate of matrix metalloproteinase-12.

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  • 1Commissariat à l'Energie Atomique, Département d'Ingénierie et d'Etudes des Protéines Bat 152, CE-Saclay, 91191 Gif/Yvette, Cedex, France.

Abstract

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 Ki 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.

PMID:
16481329
DOI:
10.1074/jbc.M600222200
[PubMed - indexed for MEDLINE]
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