Investigation of subsite preferences in aminopeptidase A (EC 3.4.11.7) led to the design of the first highly potent and selective inhibitors of this enzyme

J Med Chem. 1999 Dec 16;42(25):5197-211. doi: 10.1021/jm9903040.

Abstract

The study of the physiological roles of the membrane-bound zinc-aminopeptidase A (glutamyl aminopeptidase, EC 3.4.11.7) needs the design of efficient and selective inhibitors of this enzyme. An acute exploration of aminopeptidase A active site was performed by a combinatorial approach using (3-amino-2-mercapto-acyl)dipeptides able to fit its S(1), S(1)', and S(2)' subsites. This analysis confirmed that the S(1) subsite is optimally blocked by a glutamate or isosteric residues and demonstrated that the S(1)' subsite is hydrophobic whereas the S(2)' subsite recognizes preferentially negatively charged residues derived from aspartic acid. The optimization of these structural parameters led to the synthesis of nanomolar and subnanomolar inhibitors of aminopeptidase A such as H(3)N(+)CH(CH(2)CH(2)SO(3)(-))CH(SH)CO-Ile-(3-COOH)Pro that exhibits a K(i) of 0.87 nM. The best compounds were synthesized by a stereochemically controlled route. These first described highly potent inhibitors could allow studies about the role of physiological substrates of APA such as angiotensin II and cholecystokinin CCK(8) in the central nervous system.

MeSH terms

  • Aminopeptidases / antagonists & inhibitors
  • Aminopeptidases / metabolism*
  • Animals
  • CD13 Antigens / antagonists & inhibitors
  • CD13 Antigens / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Glutamyl Aminopeptidase
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Neprilysin / metabolism
  • Peptidyl-Dipeptidase A / drug effects
  • Peptidyl-Dipeptidase A / metabolism
  • Rabbits
  • Rats
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Stereoisomerism
  • Swine

Substances

  • Enzyme Inhibitors
  • Recombinant Proteins
  • Aminopeptidases
  • CD13 Antigens
  • Glutamyl Aminopeptidase
  • Peptidyl-Dipeptidase A
  • Neprilysin