RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites

The human somatic angiotensin converting enzyme (ACE) contains two homologo us domains, each bearing a zinc-dependent active site. All of the synthetic inhibitors of this enzyme used in clinical applications interact with thes e two active sites to a similar extent. Recently, several lines of evidence have suggested that the N-terminal active site of ACE might be involved in specific hydrolysis of some important physiological substrates, like Acety l-Seryl-Aspartyl-Lysyl-Proline, a negative regulator of hematopoietic stem cell differentiation and proliferation. These findings have stimulated stud ies aimed at identifying new ACE inhibitors able to block only one of the t wo active sites of this enzyme. By screening phosphinic peptide libraries, we discovered a phosphinic peptide Ac-Asp-((L))Phe psi(PO2-CH2)((L))Ala-Ala -NH2, called RXP 407, which is able to differentiate the two ACE active sit es, with a dissociation constant three orders of magnitude lower for the N- domain of the enzyme. The usefulness of a combinatorial chemistry approach to develop nerv lead structures is underscored by the unusual chemical stru cture of RXP 407, as compared with classical ACE inhibitors. As a highly po tent and selective inhibitor of the N-terminal active site of wild ACE (K-i = 12 nM), RXP 407, which is metabolically stable in vivo, may lead to a ne w generation of ACE inhibitors able to block in vivo only a subset of the d ifferent functions regulated by ACE.