CYCLIC-PEPTIDES WITH A PHOSPHINIC BOND AS POTENT INHIBITORS OF A ZINCBACTERIAL COLLAGENASE

A series of cyclic peptides containing a phosphinic bond were synthesi zed and evaluated as inhibitors of a zinc bacterial collagenase from C orynebacterium rathaii. Among this series of pseudopeptides of differe nt sizes of cycles, only two molecules Ia (cycto[Gly-Pro-Phe Psi(PO2CH 2)-Gly-Pro-Ahx]) and Va (cyclo[beta Ala-Pro-Phe Psi(PO2CH2)Gly-Pro-Ahx ]) were found to be rather potent inhibitors of this protease, with K- i values of 120 and 90 nM, respectively. Besides the influence of the peptide ring size, this study suggests that both the stereochemical an d the conformational properties of the pseudophenylalanine residue in these cyclic peptides may determine their potency. Interestingly, the kinetic analysis for the binding of the cyclic peptide inhibitors Ia a nd Va to the collagenase, as compared to a linear parent compound, rev eals that the lower potency of the cyclic peptides is mostly the conse quence of a lower rate constant for association to the enzyme. To our knowledge, this is the first report on cyclic phosphinic peptides and on their activities as inhibitors of a zinc protease.