Plant-derived peptides rubiscolin-6, soymorphin-6 and their c-terminal amide derivatives: Pharmacokinetic properties and biological activity
Azzurra Stefanucci, Marilisa Pia Dimmito, Gian Carlo Tenore, Stefano Pieretti, Paola Minosi, Gökhan Zengin, Chiara Sturaro, Girolamo Calò, Ettore Novellino, Angelo Cichelli, Adriano Mollica
Abstract
The aim of this work is to investigate the pharmacokinetic properties, antinociceptive and antioxidant activities of rubiscolin-6, soymorphin-6 and their C-terminal amides; The four peptides were synthesized following Fmoc-SPPS strategy to give the final peptides in excellent overall yields and purity following analytical RP-HPLC analysis. None of them shows antioxidant activity and α-tyrosinase inhibition in vitro. All compounds are able to activate G-protein coupled receptor at the δ-opioid receptor (DOR) at 100 μM concentration however, rubiscolin-6-amide exhibits significative antinociceptive effect after i.c.v. administration in the tail flick test (TF) and s.c. administration in the formalin test (FT). Rubiscolin-6 shows the best in vitro intestinal bioavailability in CaCo2 cell monolayer and stability to the brush border exopeptidases in the apical compartment. In silico experiments show the interaction of rubiscolin-6 and rubiscolin-6 amide at the binding cavity of DOR compared with the crystallographic ligand TIPP-NH2.