Molecular Basis for Omapatrilat and Sampatrilat Binding to NeprilysinImplications for Dual Inhibitor Design with Angiotensin-Converting Enzyme

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.