Synthesis, Structure-Activity Studies, and Therapeutic Potential of Met-enkephalin Derivatives

One potential drug with analgesic, anticancer, and immune-enhancing properties is the endogenous pentapeptide M-ENK (opioid growth factor, OGF). A significant problem limiting its therapeutic application is its low bioavailability and short half-life in human plasma. Therefore, new analogues, as well as suitable delivery vehicles and administration routes for these potential drugs, are being sought. This article reviews the synthesis methods for OGF and its analogues, as well as the structure-activity relationships. Among other things, it describes: Compounds obtained by shortening or modifying the amino acid sequence in the peptide chain, methylated derivatives, compounds with hydrazine and phenylhydrazine, and with quercetin and resveratrol, which exhibit antioxidant properties, as well as derivatives containing bifunctional adamantane analogs, glycosylated derivatives with increased bioavailability, derivatives containing trifluoromethylamino acid residues in the G2 or G3 position, alkylamide derivatives, cyclic analogs containing thiazoles, cyclic peptidomimetic analogs, and the OGF-Gem conjugate. The M-ENK nanocarrier with RGD molecules is also presented for the controlled delivery of OGF to cancer cells. We highlight OGF and its derivatives in anticancer, analgesic, and immunomodulatory studies, and the potential for use in the treatment of other diseases, such as neurodegenerative (Alzheimer's, Parkinson's), diabetes, and viral diseases. The therapeutic potential of OGF is very large; therefore, it can be expected that the synthesis of new analogues and conjugates with used chemotherapeutic agents will be continued.