Development of Selective Inhibitors and Substrate of Matrix Metalloproteinase-12

• Published in: The Journal of biological chemistry Vol. 281; no. 16; pp. 11152 - 11160
• Main Authors: Devel, Laurent, Rogakos, Vassilis, David, Arnaud, Makaritis, Anastasios, Beau, Fabrice, Cuniasse, Philippe, Yiotakis, Athanasios, Dive, Vincent
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.04.2006; American Society for Biochemistry and Molecular Biology
• Subjects: Drug Design; Enzyme Inhibitors - chemistry; Glutamic Acid - chemistry; Humans; Kinetics; Lysine - chemistry; Matrix Metalloproteinase 12; Matrix Metalloproteinases - metabolism; Metalloendopeptidases - antagonists & inhibitors; Metalloendopeptidases - chemistry; Metalloendopeptidases - physiology; Models, Chemical; Models, Molecular; Peptide Library; Peptides - chemistry; Protein Conformation; Protein Structure, Tertiary; Substrate Specificity; Threonine - chemistry; Time Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M600222200

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.