Semax and Selank inhibit the enkephalin-degrading enzymes of human serum
Kost NV, Sokolov OYu, Gabaeva MV, Grivennikov IA, Andreeva LA, Myasoedov NF
Russian Journal of Bioorganic Chemistry (2001)
The foundational mechanism paper: Semax and Selank inhibit human serum enkephalin-degrading enzymes in vitro with IC50 values of 10 µM and 20 µM respectively — roughly three orders of magnitude more potent than the standard inhibitor puromycin (IC50 10 mM).
The foundational mechanism paper underpinning the Zozulya 2008 clinical trial's biomarker rationale. The Kost / Sokolov / Zozulya group at the Russian Academy of Medical Sciences National Research Center for Mental Health, working with the Andreeva / Myasoedov peptide-synthesis program at the Institute of Molecular Genetics, showed in human serum in vitro that both Semax (Met-Glu-His-Phe-Pro-Gly-Pro) and Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) inhibit enzymes that hydrolyse leu-enkephalin, with dose-dependent IC50 values of 10 µM (Semax) and 20 µM (Selank).
For comparison, puromycin — a classical aminopeptidase inhibitor — had an IC50 of 10 mM in the same assay, i.e. roughly three orders of magnitude weaker. Bacitracin and other standard peptidase inhibitors were also outperformed. Structure-activity follow-up showed that pentapeptide fragments retained inhibitory activity but tri-, tetra-, and hexapeptide fragments did not, locating the activity in the C-terminal Pro-Gly-Pro extension common to both peptides.
The paper proposes that one mechanism of biological activity of these regulatory heptapeptides is the inhibition of enzymes that degrade endogenous enkephalins and other regulatory peptides — the molecular underpinning subsequently invoked in the Zozulya 2008 clinical trial's leu-enkephalin half-life biomarker.
This is an in vitro assay in human serum, not in CNS tissue, and does not directly demonstrate that the same inhibition occurs in vivo at therapeutic intranasal doses. The IC50 values (10–20 µM) sit substantially above the systemic concentrations achievable with the 2.7 mg/day intranasal dose used in the Zozulya 2008 trial — bridging the in vitro biochemistry to the in vivo clinical biomarker effect requires the additional assumption that local concentrations at relevant sites can reach the inhibitory range, or that partial inhibition at lower concentrations is sufficient.
The paper does not identify the specific enzyme inhibited (multiple enkephalin-degrading enzymes operate in serum: neutral endopeptidase / neprilysin, aminopeptidase N, dipeptidyl peptidase III, and angiotensin-converting enzyme), only that crude serum hydrolysis activity is inhibited. Single-laboratory, single-group work; Western independent replication of the enzyme-inhibition result is not present in the English literature. Abstract-only extraction; full body text paywalled.
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