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.
Through the development of a new chemical strategy, aminophosphinic peptides containing a pseudoglutamyl residue (Glu Psi(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, Glu Psi(PO2-CH2)Leu-Ala, displayed a Ki value of 0.8 nM for APA, but was much less effective in blocking aminopeptidase N (APN) (Ki = 31 microM). The critical role of the glutamyl residue in this phosphinic peptide, both in potency and selectivity, is exemplified by the P1 position analogue, Ala Psi(PO2-CH2)Leu-Ala, which exhibited a Ki value of 0.9 microM toward APA but behaved as a rather potent inhibitor of APN (Ki = 25 nM). Glu Psi(PO2-CH2)Leu-Xaa peptides are poor inhibitors of angiotensin converting enzyme (Ki values higher than 1 microM). 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 microM. 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.
Georgiadis
D
D
Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistiomiopolis, Zografou, Athens, Greece.
Vazeux
G
G
Llorens-Cortes
C
C
Yiotakis
A
A
Dive
V
V
D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018826:CD13 Antigens / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018698:Glutamic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D043384:Glutamyl Aminopeptidase; D006801:Humans; D015260:Neprilysin / Q000037:antagonists & inhibitors; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010721:Phosphinic Acids / Q000737:chemistry* / Q000494:pharmacology; D011817:Rabbits; D015032:Zinc / Q000737:chemistry
D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010455:Peptides; D010721:Phosphinic Acids; D018698:Glutamic Acid; D000626:Aminopeptidases; D018826:CD13 Antigens; D043384:Glutamyl Aminopeptidase; D015260:Neprilysin; D015032:Zinc