Neutral endopeptidase (neprilysin)

Neprilysin, also known as neutral endopeptidase (NEP), enkephalinase, CALLA, or CD10, is a mammalian type II integral membrane zinc endopeptidase, which inactivates different types of bioactive peptides. A particular characteristic of NEP is the restricted active site that prevents the access of large compounds and explains its oligopeptidase activity. Among the active oligopeptide substrates for NEP, there are opioid peptides (such as enkephalins), natriuretic peptides, bradykinin, endothelin-1 (ET-1), adrenomedullin, substance P, glucagon, glucagon-like peptide, somatostatin, and angiotensin I (AI) and II (AII). All these substrates highlight the important role of NEP in the modulation of nociceptive and pressor responses, stimulating a growing interest in developing inhibitors of this enzyme to treat a variety of conditions varying from cardiovascular diseases to pain. Over the years, different NEP inhibitors were identified, including thiorphan, candoxatril, ecadotril, and sacubitril. However, they failed in showing efficacy probably due to the increased levels of AII and ET-1, which degradation is also mediated by NEP. For this reason, the NEP block alone appears unable to induce cardiovascular benefits but necessitates of a multitarget action on more vasoactive peptidases. This chapter summarizes the NEP structure and function, and its physiologic/pathologic role. Moreover, characteristics of NEP inhibitors in clinical use or development were reported.