Neprilysin (NEP) (NEP)

Neprilysin (NEP), also known as CD10 or membrane metallo-endopeptidase (MME), is a zinc-dependent membrane-bound metalloprotease that plays a critical role in the degradation of various bioactive peptides [1, 4]. Its primary substrates include natriuretic peptides (ANP, BNP, CNP), bradykinin, substance P, enkephalins, and amyloid-beta [1, 8]. In the cardiovascular system, neprilysin inhibition increases the levels of natriuretic peptides, which promote vasodilation, natriuresis, and diuresis, making it a key therapeutic target for heart failure [5, 7]. The most prominent clinical application is the use of sacubitril, a neprilysin inhibitor, in combination with the angiotensin receptor blocker valsartan (Entresto) for treating heart failure with reduced ejection fraction [1, 13]. Beyond cardiovascular disease, neprilysin is a well-known biomarker in oncology, where it is referred to as CD10 or CALLA, and is used to identify specific types of leukemia and lymphoma [4, 10]. It is also studied for its role in Alzheimer's disease due to its ability to degrade amyloid-beta plaques, although therapeutic strategies in this area are still evolving [3, 10]. Additionally, neprilysin is involved in the regulation of inflammatory responses and pain perception through the processing of substance P and enkephalins [8, 10]. The enzyme is widely expressed in tissues such as the kidneys, lungs, and brain, reflecting its diverse physiological roles [1, 8]. Therapeutic challenges include the risk of angioedema when combined with ACE inhibitors and theoretical concerns regarding long-term amyloid accumulation [7, 12]. Overall, neprilysin represents a versatile target with significant impact on cardiovascular and oncological medicine [10, 12].

Other names

Membrane metallo-endopeptidaseMMECD10Common acute lymphoblastic leukemia antigenCALLANeutral endopeptidaseEnkephalinaseAtriopeptidaseSFESkin fibroblast elastase

Neprilysin inhibitors block the enzymatic degradation of natriuretic peptides (ANP, BNP, CNP) and other vasoactive peptides, thereby increasing their circulating levels and enhancing their vasodilatory, natriuretic, and diuretic effects while counteracting the renin-angiotensin-aldosterone system.