Inhibition of matrix metalloproteinases by peptidyl hydroxamic acids

Biochem Biophys Res Commun. 1994 Mar 30;199(3):1442-6. doi: 10.1006/bbrc.1994.1392.

Abstract

Synthetic inhibitors of interstitial collagenase, tri- and tetrapeptidyl hydroxamic acids, have been developed and tested for their inhibitory activities against human matrix metalloproteinases. A water soluble inhibitor, p-NH2-Bz-Gly-Pro-D-Leu-D-Ala-NHOH (FN-439) inhibited interstitial and granulocyte collagenases, granulocyte gelatinase and skin fibroblast stromelysin with IC50 of 1 x 10(-6) M, 3.0 x 10(-5) M and 1.5 x 10(-4), respectively, but not thermolysin and serine proteinases. FN-439 was found to retain its inhibitory activity against matrix metalloproteinases even after prolonged incubation with pronase or human granulocyte elastase, indicating a favorite candidate of the inhibitor to modulate metalloproteinase activities in vivo.

MeSH terms

  • Amino Acid Sequence
  • Fibroblasts / enzymology
  • Gelatinases / antagonists & inhibitors
  • Gelatinases / blood
  • Granulocytes / enzymology
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Kinetics
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase Inhibitors
  • Metalloendopeptidases / antagonists & inhibitors*
  • Molecular Sequence Data
  • Oligopeptides / pharmacology*
  • Protease Inhibitors / pharmacology*
  • Serine Endopeptidases / metabolism
  • Serine Proteinase Inhibitors / pharmacology*
  • Skin / enzymology
  • Structure-Activity Relationship

Substances

  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • Oligopeptides
  • Protease Inhibitors
  • Serine Proteinase Inhibitors
  • Serine Endopeptidases
  • Gelatinases
  • Metalloendopeptidases
  • Matrix Metalloproteinase 3