PLANT-DERIVED PEPTIDES RUBISCOLIN-6, SOYMORPHIN-6 AND THEIR C-TERMINAL AMIDE DERIVATIVES: PHARMACOKINETIC PROPERTIES AND BIOLOGICAL ACTIVITY

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. Rubiscolin-6 and soymorphin-6 are two exhorphins derived from spinach and soybean respectively. 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 a-tyrosinase inhibition in vitro. All compounds are able to activate G-protein coupled receptor at the d-opioid receptor (DOR) at 100 mM 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.