Phosphinic Peptide Inhibitors of Macrophage Metalloelastase (MMP-12). Selectivity and Mechanism of Binding

Author(s): C. B. Schiodt, J. Buchardt, G. E. Terp, U. Christensen, M. Brink, Y. Berger Larsen, M. Meldal, N. T. Foged

Journal Name: Current Medicinal Chemistry

Volume 8 , Issue 8 , 2001

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Pseudopeptide inhibitors of MMP-12 with a phosphinic dipeptide G {PO2 H-CH2 }L covering the P1-P1 positions originating from a combinatorial solid phase library have been identified and kinetically analysed with respect to binding mechanism and selectivity towards MMP-7, MMP-9, MMP-13 and MMP-14. One compound with a low nanomolar dissociation constant for MMP-12 showed significantly lower affinity towards all other MMPs tested compared to MMP-12. Two compounds showed selectivity against MMP-9, MMP-13 and MMP-14. One additional compound showed selectivity against MMP-7. The selectivity of these compounds could partly be rationalized by analysis of homology models of the enzymes. Truncated versions of one inhibitor spanning P2 to P2 P3 to P2 or P2 to P3 showed that interactions on both the prime and the non-prime side are important for binding. A two-step binding mechanism, with a rate limiting second step, was shown for binding of a tryptophane containing inhibitor to MMP-12 by transient state analysis, using the tryptophane residue of the inhibitor as fluorescent probe.

Keywords: collagenases (MMP-1, MMP-8 MMP-13), gelatinases (MMP-2 MMP-9), stromelysins, Phosphinic Peptide Inhibitors, Macrophage Metalloelastase (MMP-12), metalloproteinases, elastolytic MMP-7, Macrophage metalloelastase

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Article Details

Year: 2001
Page: [967 - 976]
Pages: 10
DOI: 10.2174/0929867013372670
Price: $65

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