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

Abstract

Pseudopeptide inhibitors of MMP-12 with a phosphinic dipeptide G psi[PO(2)H-CH(2)]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.

Matrix metalloproteinase 11 (MMP‐11; stromelysin‐3) and synthetic inhibitors

“…This view is consistent with the very good potency displayed by phosphinic peptides towards several zinc proteinases, [66][67][68] and MMPs in particular. [69][70][71][72][73] Finally, as compared to many other class of zinc protease inhibitors, phosphinic peptide chemistry offers the possibility of developing inhibitors able to interact with both the primed and unprimed side of the active-site cleft, allowing optimization of inhibitor selectivity by diversification of both P and P 0 positions of the inhibitors. As far as the synthesis of the phosphinic pseudodipeptidic blocks is of concern, numerous synthetic strategies have been developed and reviewed, 74,75 including building block approaches [76][77][78][79] or post-modification of phosphinopeptidic precursors.…”

Phosphinic peptides as zinc metalloproteinase inhibitors

“…As with astacin, it is expected that these selective inhibitors will be useful probes in disclosing the molecular determinants responsible for the selectivity of the N-and C-domain ACE active sites. Development of rather long phosphinic peptides covering the whole enzyme active-site cleft might be useful in developing MMP inhibitors able to differentiate one particular MMP among others [18]. To date, most of the inhibitors that have been developed bind to the S 1 to S 2 ¢ subsites of these enzymes.…”

Patent focus on cancer chemotherapeutics. IV Angiogenesis agents: April 2001 - August 2001

“…Though phosphinic acids analogues have previously been reported as MMPIs [20,21], these agents have the phosphorous group endo to the amino acid chain. No information is provided on the MMPI activity of these agents.…”