Enkephalin-degrading peptidase (EDP)

Enkephalin-degrading peptidases are a class of enzymes, most notably neprilysin (NEP) and aminopeptidase N (APN), that catalyze the hydrolysis of endogenous opioid peptides (Roques et al., 1993). These enzymes are primarily located on the plasma membranes of neurons and other tissues, where they rapidly inactivate Met-enkephalin and Leu-enkephalin (Menzies et al., 2021). By terminating enkephalin signaling at mu- and delta-opioid receptors, these peptidases play a critical role in regulating pain perception and emotional states (UniProt P08473). In addition to enkephalins, these enzymes process other bioactive peptides such as substance P, bradykinin, and natriuretic peptides, linking them to cardiovascular and inflammatory processes (StatPearls, 2023). Therapeutic targeting of these enzymes, particularly through dual enkephalinase inhibitors (DENKIs), aims to elevate local enkephalin levels to provide analgesia (Fournie-Zaluski et al., 1992). This approach is considered a promising alternative to traditional opioids because it utilizes the body's own pain-relief mechanisms, potentially reducing the risk of tolerance and addiction (Chen et al., 2015). Clinical applications include the treatment of acute and chronic pain, as well as potential uses in managing diarrhea, anxiety, and heart failure (PubMed, 2022). However, because these enzymes have broad substrate specificity, their inhibition can lead to side effects like angioedema or altered blood pressure (NIH, 2023).

Other names

EnkephalinaseNeutral endopeptidaseNeprilysinAminopeptidase NCD13MMEDual enkephalinaseAlanyl aminopeptidase

Inhibition of the enzymatic cleavage of enkephalins, thereby increasing the half-life and local concentration of endogenous opioid peptides to enhance their natural analgesic and mood-stabilizing effects (Roques et al., 1993).