Inhibition studies of some serine and thiol proteinases by new leupeptin analogues

J Med Chem. 1993 Apr 16;36(8):1084-9. doi: 10.1021/jm00060a016.

Abstract

Fifteen tripeptide analogues of leupeptin containing either a C-terminal argininal or lysinal were synthesized. The synthetic analogues were tested, using spectrophotometric assay techniques, as inhibitors of trypsin, kallikrein, thrombin, plasmin, and cathepsin B. The lysinal analogues were fairly selective as inhibitors of cathepsin B activity. Acetyl-L-leucyl-L-valyl-L-lysinal (21) showed a stronger inhibition of cathepsin B (IC50 = 4 nanomolar) than leupeptin. Acetyl-L-phenylalanyl-L-valyl-L-argininal (2i) was found to be a good inhibitor of cathepsin B (IC50 = 0.039 microM), thrombin (IC50 = 1.8 microM), and plasmin (IC50 = 2.2 microM).

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cathepsin B / antagonists & inhibitors
  • Cattle
  • Cysteine Proteinase Inhibitors / chemical synthesis*
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology
  • Humans
  • Leupeptins / chemical synthesis*
  • Leupeptins / chemistry
  • Leupeptins / pharmacology
  • Molecular Sequence Data
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology
  • Spectrophotometry
  • Structure-Activity Relationship

Substances

  • Cysteine Proteinase Inhibitors
  • Leupeptins
  • Oligopeptides
  • Serine Proteinase Inhibitors
  • Cathepsin B