Potency and selectivity of RXP407 on human, rat, and mouse angiotensin-converting enzyme.
By screening phosphinic peptide libraries, we recently reported the discovery of RXP407 (Ac-Asp-PheY(PO2-CH2)LAla-Ala-NH2), a potent N-domain-selective inhibitor of recombinant human angiotensin-converting enzyme (ACE). Preliminary studies to evaluate the in vivo activity of RXP407 in rat led us to suspect possible differences in the binding property of RXP407 between human and rat ACE. The aim of the present study was thus to determine the potency of RXP407 toward rat and mouse ACEs, as compared to non-recombinant human ACE, and to assess the efficacy of this inhibitor in discriminating between the N- and C-domains of these ACE enzymes. By comparing the ability of RXP407 to block purified somatic and germinal ACE from mice, RXP407 was shown to be a potent N-domain-selective inhibitor of mouse somatic ACE, a behavior similar to that observed with human somatic ACE. In contrast, RXP407 appeared less potent toward purified ACE from rat and furthermore was unable to block ACE activity present in crude rat plasma. This study demonstrated that for further evaluation of the in vivo efficacy of RXP407, mice rather than rats should be used as the animal model. Thus, following the change in the Ac-S-D-K-P plasmatic levels, after i.v. injection of RXP407 to mice, will permit the potency and selectivity of this novel ACE inhibitor to be assessed.
CEA, Département d'Ingénierie et d'Etudes des Protéines, DIEP Bât 152, F-91191 Cedex, Gif/Yvette, France.
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D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D004347:Drug Interactions; D006131:Growth Inhibitors / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000097:blood* / Q000187:drug effects; D010721:Phosphinic Acids / Q000494:pharmacology*; D051381:Rats; D013045:Species Specificity; D013737:Testis / Q000201:enzymology
D000806:Angiotensin-Converting Enzyme Inhibitors; D006131:Growth Inhibitors; D009842:Oligopeptides; D010721:Phosphinic Acids; C118733:RXP 407; D007703:Peptidyl-Dipeptidase A; C058504:goralatide