Binding experiments have shown that Angiotensin Converting Enzyme inhibitors (ACE-Ins) have high chemical affinity for binding sites of human somatic ACE (hsACE). The enzyme has 2 natural substrates and catalytic domains: one cleaving angiotensin-I (Ang-I) and the other inactivating bradykinin 1-9 (Bk). AIM: To test binding selectivity of various ACE-Ins - namely Enalaprilat (E), Perindoprilat (P), Quinaprilat (Q), Ramiprilat (R), Trandolaprilat (T) – for specific Ang-I and Bk binding sites of hsACE. Single displacement binding assays showed the following IC50 for ACE-Ins and hsACE natural substrates: Q: 0.35 nM, T: 0.57 nM, R: 0.76 nM, P: 1.05 nM, E:1.94 nM, Ang-I: 2.65 microM and Bk: 1.31 microM. The order of binding affinity of ACE-Ins to hsACE is: Q>T>R>P>E; (2) All ACE-Ins have a higher affinity for Bk respect to Ang-I binding sites, the order of binding affinity being E>Q>T>R>P for Ang-I and Q>E>T>R>P for Bk binding sites, respectively; (3) P is the ACE-In with the highest selectivity for Bk versus Ang-I binding sites, (the order of Bk/Ang-I selectivity being P>R>Q>T>E). These results support the hypothesis that affinity differences of ACE-Ins towards sites for Bk degradation exist and may constitute the biochemical grounds in explaining differences obtained in secondary prevention of coronary artery disease.

The ACE-inhibitor Perindoprilat has high selectivity for bradykinin binding sites of human somatic ACE

FERRARI, Roberto;CECONI, Claudio
2006

Abstract

Binding experiments have shown that Angiotensin Converting Enzyme inhibitors (ACE-Ins) have high chemical affinity for binding sites of human somatic ACE (hsACE). The enzyme has 2 natural substrates and catalytic domains: one cleaving angiotensin-I (Ang-I) and the other inactivating bradykinin 1-9 (Bk). AIM: To test binding selectivity of various ACE-Ins - namely Enalaprilat (E), Perindoprilat (P), Quinaprilat (Q), Ramiprilat (R), Trandolaprilat (T) – for specific Ang-I and Bk binding sites of hsACE. Single displacement binding assays showed the following IC50 for ACE-Ins and hsACE natural substrates: Q: 0.35 nM, T: 0.57 nM, R: 0.76 nM, P: 1.05 nM, E:1.94 nM, Ang-I: 2.65 microM and Bk: 1.31 microM. The order of binding affinity of ACE-Ins to hsACE is: Q>T>R>P>E; (2) All ACE-Ins have a higher affinity for Bk respect to Ang-I binding sites, the order of binding affinity being E>Q>T>R>P for Ang-I and Q>E>T>R>P for Bk binding sites, respectively; (3) P is the ACE-In with the highest selectivity for Bk versus Ang-I binding sites, (the order of Bk/Ang-I selectivity being P>R>Q>T>E). These results support the hypothesis that affinity differences of ACE-Ins towards sites for Bk degradation exist and may constitute the biochemical grounds in explaining differences obtained in secondary prevention of coronary artery disease.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/525521
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