Cyclic peptides with a phosphinic bond as potent inhibitors of a zinc bacterial collagenase

J Med Chem. 1994 Aug 19;37(17):2713-20. doi: 10.1021/jm00043a011.

Abstract

A series of cyclic peptides containing a phosphinic bond were synthesized and evaluated as inhibitors of a zinc bacterial collagenase from Corynebacterium rathaii. Among this series of pseudopeptides of different sizes of cycles, only two molecules Ia (cyclo[Gly-Pro-Phe psi(PO2CH2)-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 Ki values of 120 and 90 nM, respectively. Besides the influence of the peptide ring size, this study suggests that both the stereochemical and 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 and Va to the collagenase, as compared to a linear parent compound, reveals that the lower potency of the cyclic peptides is mostly the consequence 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.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Corynebacterium / enzymology*
  • Indicators and Reagents
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Matrix Metalloproteinase Inhibitors*
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / pharmacology*
  • Phosphines*
  • Protein Binding
  • Protein Conformation
  • Structure-Activity Relationship
  • Zinc / metabolism

Substances

  • Indicators and Reagents
  • Matrix Metalloproteinase Inhibitors
  • Peptides, Cyclic
  • Phosphines
  • Zinc