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 P-1 position

Through the development of a new chemical strategy, aminophosphinic peptide s containing a pseudoglutamyl residue (Glu Psi(PO2-CH2)Leu-Xaa) in the N-te rminal position were synthesized and evaluated as inhibitors of aminopeptid ase A (APA). The most potent inhibitor developed in this study, Glu Psi(PO2 -CH2)Leu-Ala, displayed a K-i value of 0.8 nM for APA, but was much less ef fective in blocking aminopeptidase N (APN) (K-i = 31 mu M). The critical ro le of the glutamyl residue in this phosphinic peptide, both in potency and selectivity, is exemplified by the PI position analogue, Ala Psi(PO2-CH2)-L eu-Ala, which exhibited a Ki value of 0.9 mu M toward APA but behaved as a rather potent inhibitor of APN (K-i = 25 nM). Glu Psi(PO2-CH2)Leu-Xaa pepti des are poor inhibitors of angiotensin converting enzyme (Ki values higher than 1 mu M). Depending on the nature of the Xaa residue, the potency of th ese phosphinic peptides toward neutral endopeptidase 24-11 varied from 50 n M to 3 mu M. In view of the in vivo role of APA in the formation of brain a ngiotensin III, one of the main effector peptides of the renin angiotensin system in the central nervous system, highly potent and selective inhibitor s of APA may find important therapeutic applications soon.