Abstract
Neprilysin (NEP) and angiotensin-converting enzyme (ACE) are two key zinc-dependent metallopeptidases in the natriuretic peptide and kinin systems and renin–angiotensin–aldosterone system, respectively. They play an important role in blood pressure regulation and reducing the risk of heart failure. Vasopeptidase inhibitors omapatrilat and sampatrilat possess dual activity against these enzymes by blocking the ACE-dependent conversion of angiotensin I to the potent vasoconstrictor angiotensin II while simultaneously halting the NEP-dependent degradation of vasodilator atrial natriuretic peptide. Here, we report crystal structures of omapatrilat, sampatrilat, and sampatrilat-ASP (a sampatrilat analogue) in complex with NEP at 1.75, 2.65, and 2.6 Å, respectively. A detailed analysis of these structures and the corresponding structures of ACE with these inhibitors has provided the molecular basis of dual inhibitor recognition involving the catalytic site in both enzymes. This new information will be very useful in the design of safer and more selective vasopeptidase inhibitors of NEP and ACE for effective treatment in hypertension and heart failure.
Highlights
Cardiovascular disease (CVD) is responsible for ∼30% of all deaths worldwide, most of which occur in developing countries
Many patients receiving treatment suffer from severe side effects such as angioedema and persistent cough and still eventually develop nephropathy, retinopathy, and heart failure.[2−4] The renin-angiotensin-aldosterone system (RAAS), the endothelin system (ES), and the natriuretic peptides and kinin system (NPKS) play important roles in blood pressure regulation; peptidases and receptors within these systems are important drug targets for the treatment of hypertension.[5]
Bradykinin is degraded by both angiotensin-converting enzyme (ACE) and NEP as well as aminopeptidase 2 (APP2), a third enzyme inhibited by omapatrilat;[13] as such, inhibiting these three enzymes simultaneously exacerbates the problems associated with the buildup of bradykinin
Summary
Cardiovascular disease (CVD) is responsible for ∼30% of all deaths worldwide, most of which occur in developing countries. Many patients receiving treatment suffer from severe side effects such as angioedema and persistent cough and still eventually develop nephropathy, retinopathy, and heart failure.[2−4] The renin-angiotensin-aldosterone system (RAAS), the endothelin system (ES), and the natriuretic peptides and kinin system (NPKS) play important roles in blood pressure regulation; peptidases and receptors within these systems are important drug targets for the treatment of hypertension.[5]. The poor safety profile of omapatrilat stalled the development of this otherwise
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