ENDOPEPTIDASE-3.4.24.11 CONVERTS ARBOXY-3-PHENYLPROPYL-ALA-ALA-PHE-P-CARBOXYANILIDE INTO A POTENT INHIBITOR OF ANGIOTENSIN-CONVERTING ENZYME

It was reported recently that arboxy-3-phenylpropyl-Ala-Ala-Phe-p-carb oxyanilide (CPP-A-A-F-pAB), an inhibitor of endopeptidase 3.4.24.15 (E -24.15), also inhibits angiotensin-converting enzyme (ACE) from rabbit lung. We have found that this compound is without effect on ACE purif ied from pig kidney, at a concentration some 1000-fold greater than th e K(i) reported for inhibition of the enzyme from lung. However, prein cubation of CPP-A-A-F-pAB with neutral endopeptidase 3.4.24.11 (E-24.1 1) does result in potent inhibitory effects on ACE. We have shown this to be due to formation of a fragment, CPP-A-A, the structure of which is closely related to ACE inhibitors such as enalaprilat. CPP-A-A was found to be a potent inhibitor of pig ACE. Under the conditions used it had an IC50 value of 1.6 x 10(-8) M, compared with the value obtain ed for captopril of 7.5 x 10(-10) M. These results have important impl ications for studies of E-24.15 when using CPP-A-A-F-pAB in vivo or in crude tissue extracts where E-24.11 might also be present.