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

Authors: Schiodt C.B.; Buchardt J.; Terp G.E.; Christensen U.; Brink M.; Larsen Y.Berger; Meldal M.; Foged N.T.

Source: Current Medicinal Chemistry, Volume 8, Number 8, July 2001 , pp. 967-976(10)

Publisher: Bentham Science Publishers

Abstract:

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

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/0929867013372670

Publication date: 2001-07-01

• Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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• By this author: Schiodt C.B. ;  Buchardt J. ;  Terp G.E. ;  Christensen U. ;  Brink M. ;  Larsen Y.Berger ;  Meldal M. ;  Foged N.T.

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