- Neprilysin (also known as neutral endopeptidase, NEP, CD10, or MME for membrane metallo-endopeptidase) is a zinc-dependent metalloprotease that plays a critical role in the regulation of bioactive peptide levels in various physiological systems. It is a type II integral membrane protein with its active site facing the extracellular space, allowing it to cleave and inactivate a wide range of peptide substrates, including enkephalins, substance P, bradykinin, atrial natriuretic peptide (ANP), endothelin, and amyloid-β peptides.
- Neprilysin is expressed in many tissues, with high levels in the kidney, lungs, intestines, brain, and immune system cells. It cleaves peptides at the amino side of hydrophobic residues, and its enzymatic activity depends on a zinc ion at the active site, which coordinates a water molecule necessary for peptide bond hydrolysis. It belongs to the M13 family of metallopeptidases.
- Functionally, neprilysin serves as a key regulator of peptide-mediated signaling pathways. In the cardiovascular system, it degrades vasoactive peptides like ANP and bradykinin, thereby modulating blood pressure and fluid homeostasis. In the nervous system, it inactivates neuropeptides such as enkephalins and substance P, influencing pain perception, neuronal signaling, and inflammation.
- Neprilysin has garnered major attention in neurodegenerative research, particularly in Alzheimer’s disease, due to its ability to degrade amyloid-β (Aβ) peptides. Impaired neprilysin activity or expression has been linked to Aβ accumulation and plaque formation in the brain, making it a therapeutic target for enhancing Aβ clearance in Alzheimer’s disease.
- Clinically, neprilysin is also targeted in the treatment of heart failure. Drugs such as sacubitril, which inhibits neprilysin, are used in combination with angiotensin receptor blockers (ARNIs) to prolong the activity of beneficial natriuretic peptides, thereby improving cardiovascular outcomes.
- In summary, neprilysin is a critical membrane-bound metalloprotease that regulates diverse physiological functions through the degradation of bioactive peptides. Its roles in cardiovascular regulation, pain modulation, and neurodegeneration make it a key focus of both basic and translational biomedical research.
