ABSTRACT
Neutral endopeptidase-24.11 (NEP, neprilysin, EC 3.4.24.11) is a zinc metallopeptidase with a thermolysin-like specificity for cleaving peptides on theN-terminal side of hydrophobic residues. The cloning of this ectoenzyme and subsequent sitedirected mutagenesis experiments have shown that, as well as having a similar specificity to thermolysin, it also has a similar active site organization, and X-ray crystallographic data for the bacterial enzyme has been invaluable for designing NEP inhibitors. The clinical interest in these inhibitors derives from the actions of NEP, in conjunction with aminopeptidase N (APN), in degrading the enkephalins and also its role in degrading atrial natriuretic peptide. Dual NEP/APN inhibitors completely block enkephalin metabolism and have strong antinociceptive properties. Similarly, dual inhibitors of NEP and angiotensin converting enzyme (ACE) are potent antihypertensives, resulting from simultaneously increasing the circulating levels of atrial natriuretic peptide, due to NEP inhibition, and decreasing the circulating levels of angiotensin II, due to ACE inhibition. The design of these dual inhibitors and their potential advantages over currently available analgesics and antihypertensives is discussed.
