Potent and Selective Inhibition of Zinc Aminopeptidase A (EC 3.4.11.7, APA) by Glutamyl Aminophosphinic Peptides: Importance of Glutamyl Aminophosphinic Residue in the P1 Position

Abstract

Through the development of a new chemical strategy, aminophosphinic peptides containing a pseudoglutamyl residue (GluΨ(PO₂-CH₂)Leu-Xaa) in the N-terminal position were synthesized and evaluated as inhibitors of aminopeptidase A (APA). The most potent inhibitor developed in this study, GluΨ(PO₂-CH₂)Leu-Ala, displayed a K_i value of 0.8 nM for APA, but was much less effective in blocking aminopeptidase N (APN) (K_i = 31 μM). The critical role of the glutamyl residue in this phosphinic peptide, both in potency and selectivity, is exemplified by the P₁ position analogue, AlaΨ(PO₂-CH₂)Leu-Ala, which exhibited a K_i value of 0.9 μM toward APA but behaved as a rather potent inhibitor of APN (K_i = 25 nM). GluΨ(PO₂-CH₂)Leu-Xaa peptides are poor inhibitors of angiotensin converting enzyme (K_i values higher than 1 μM). Depending on the nature of the Xaa residue, the potency of these phosphinic peptides toward neutral endopeptidase 24−11 varied from 50 nM to 3 μM. In view of the in vivo role of APA in the formation of brain angiotensin III, one of the main effector peptides of the renin angiotensin system in the central nervous system, highly potent and selective inhibitors of APA may find important therapeutic applications soon.