Inhibition of aminopeptidases by amastatin and bestatin derivatives. Effect of inhibitor structure on slow-binding processes

J Med Chem. 1984 Apr;27(4):417-22. doi: 10.1021/jm00370a001.


Amastatin [(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl-L-valyl-L-valyl-L- aspartic acid] and bestatin [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-L-leucine] are slow-binding, competitive inhibitors of aminopeptidase M (AP-M) with net inhibition constants (Ki) of 1.9 X 10(-8) and 4.1 X 10(-6) M, respectively. The effect of inhibitor structure on net Ki and on slow-binding inhibition was evaluated for analogues of both inhibitors on AP-M and leucine aminopeptidase (LAP). The (2S)-hydroxyl group contributes to the stabilization of a collision complex [EI], which is formed rapidly. In contrast, increasing the peptide chain length of the inhibitor produces more potent inhibitors as a consequence of a slower binding process. A statine analogue of amastatin [(3S,4S)-Sta-Val-Val-Asp] stimulated rather than inhibited LAP. AP-M binds tri- and tetrapeptide inhibitors more strongly than dipeptide inhibitors, whereas LAP binds dipeptide inhibitors more strongly. The difference in binding can be used to distinguish cytosolic from membrane-bound aminopeptidases.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aminopeptidases / antagonists & inhibitors*
  • Anti-Bacterial Agents* / pharmacology*
  • Antibiotics, Antineoplastic / pharmacology
  • CD13 Antigens
  • Kinetics
  • Leucine / analogs & derivatives*
  • Leucine / pharmacology
  • Leucyl Aminopeptidase / antagonists & inhibitors*
  • Oligopeptides / pharmacology
  • Peptides*
  • Structure-Activity Relationship


  • Anti-Bacterial Agents
  • Antibiotics, Antineoplastic
  • Oligopeptides
  • Peptides
  • amastatin
  • Aminopeptidases
  • Leucyl Aminopeptidase
  • CD13 Antigens
  • Leucine
  • ubenimex