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Molecular basis for omapatrilat and sampatrilat binding to neprilysin – implications for dual inhibitor design with angiotensin converting enzyme

DOI: 10.1021/acs.jmedchem.0c00441 DOI Help

Authors: Urvashi Sharma (University of Bath) , Gyles E. Cozier (University of Bath) , Edward D. Sturrock (University of Cape Town) , K. Ravi Acharya (University of Bath)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: April 2020
Diamond Proposal Number(s): 17212

Open Access Open Access

Abstract: Neprilysin (NEP) and angiotensin-1 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-dependant conversion of angiotensin I to the potent vasoconstrictor angiotensin II while simultaneously halting the NEP-dependant 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 1.75Å, 2.65Å and 2.6Å, 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.

Journal Keywords: Omapatrilat; sampatrilat; neprilysin; angiotensin-1 converting enzyme; neutral endopeptidase; crystallography; enzyme kinetics; enzyme structure; metalloprotease

Diamond Keywords: Cardiovascular Disease; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 30/04/2020 14:04


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Biochemistry Catalysis Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)