Surface Plasmon Resonance Analysis of the Binding Mechanism of Pharmacological and Peptidic Inhibitors to Human Somatic Angiotensin I-Converting Enzyme

Abstract : Somatic angiotensin I-converting enzyme (ACE) possesses two catalytic domains and plays a major role in the regulation of blood pressure, thus representing a therapeutic target for the treatment of hypertension. We present a comprehensive surface plasmon resonance (SPR) study of the interaction of human somatic ACE with the pharmacological inhibitors captopril and lisinopril, the bradykinin potentiating peptide BPP-11b, and the food peptidic inhibitors from bovine alpha(s2)-casein, F(174)ALPQYLK(181) and F(174)ALPQY(179). SPR binding curves recorded with the high potency inhibitors captopril, lisinopril, and BPP-11b were evaluated both by regression analysis and by kinetic distribution analysis. The results indicated that captopril and lisinopril bound ACE with two K-D's differing by a factor 10-20 and >30, respectively (lowest K-D = 0.1-0.3 nM for both inhibitors). This shows, for the first time in a direct binding assay with the two-domain enzyme, the existence of two binding modes of the pharmacological inhibitors, presumably with the two ACE domains. The BPP-11b ACE binding curves were complex but showed a predominant interaction with K-D in the nanomolar range. The caseinopeptides, known to inhibit ACE with an IC50 of 4.3 mu M, bound to ACE with K-D = 3-4 mu M. Mapping of the F(174)ALPQY(179) binding site on ACE by sequential binding studies using captopril or BPP-11b indicated that it bound to (or near) the two active sites of ACE, in agreement with the stoichiometry of 2 determined from data fitting. Our results provide a detailed characterization of ACE-inhibitor binding modes and validate SPR for predicting the inhibitory potential of new compounds.
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Biochemistry, American Chemical Society, 2013, 52 (48), pp.8722-8731. 〈10.1021/bi4006144〉
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Soumis le : jeudi 13 juillet 2017 - 10:52:39
Dernière modification le : mercredi 12 décembre 2018 - 15:32:05

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Faiza Zidane, Gabrielle Zeder-Lutz, Danièle Altschuh, Jean-Michel Girardet, Laurent Miclo, et al.. Surface Plasmon Resonance Analysis of the Binding Mechanism of Pharmacological and Peptidic Inhibitors to Human Somatic Angiotensin I-Converting Enzyme. Biochemistry, American Chemical Society, 2013, 52 (48), pp.8722-8731. 〈10.1021/bi4006144〉. 〈hal-01561652〉

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