Hydroxamate derivatives of substrate-analogous peptides containing aminomalonic acid are potent inhibitors of matrix metalloproteinases

FEBS Lett. 1998 Oct 2;436(2):209-12. doi: 10.1016/s0014-5793(98)01128-4.

Abstract

Novel peptides containing the sequence -Pro-Leu-Ama(NHOH)- were synthesized and characterized by spectroscopic techniques. Their inhibitory properties towards the activated form of native human gelatinase B (MMP-9) and the catalytic domain of neutrophil collagenase (cdMMP-8) were determined. The most effective inhibitor synthesized exhibits Ki values of 2 x 10(-6) M (cdMMP-8) and 5 x 10(-9) M (MMP-9) thus attaining interesting discrimination between the tested metalloproteinases. A most important feature of this type of inhibitor is its peptide nature making the compounds similar to natural substrates. In spite of the peptide character of the inhibitors synthesized, the P1-P1'-peptide bond shows a high resistance to cleavage by the proteinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology*
  • Kinetics
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase Inhibitors*
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • Oligopeptides
  • Protease Inhibitors
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase 9