Peptides Livagen and Epitalon Inhibit Opioid-Degrading Enzymes in Human Blood

The endogenous opioid system plays a crucial role in regulating pain, mood, and stress response, with enkephalins (natural opioid peptides) being key players. However, these beneficial peptides are rapidly broken down by enkephalin-degrading enzymes in the body, limiting their therapeutic potential. This study investigated whether the synthetic peptide bioregulators Livagen and Epitalon could modulate the activity of these enzymes or interact directly with opioid receptors.

The study found that both Livagen and Epitalon significantly inhibited the activity of enkephalin-degrading enzymes present in human serum. Livagen demonstrated remarkable potency, with an IC50 (half maximal inhibitory concentration) of just 20 µM, indicating it required a much lower concentration to achieve 50% enzyme inhibition. In contrast, Epitalon was considerably less potent, showing an IC50 of 500 µM, meaning it was 25 times less potent than Livagen in inhibiting these enzymes. Notably, Livagen proved to be more effective at inhibiting these enzymes compared to well-known peptidase inhibitors such as puromycin, leupeptin, and D-PAM. Crucially, neither Livagen nor Epitalon showed any detectable interaction with mu- or delta-opioid receptors in the rat brain membrane fraction, suggesting their mechanism is solely through enzyme inhibition rather than direct receptor binding.