Development of a novel potent peptidyl platelet preserving agent: molecular design and biologic activity

This paper reports the molecular design of potent peptidyl platelet preserving agents. The principal structural feature of the designed agents has an RGD(Arg-Gly-Asp) sequence in a molecule, which is the adhesive site of adhesive proteins, such as fibrinogen. From conformational analyses and inhibitory effects on adhesion and aggregation of platelets, the logical design criteria aimed at enhanced antiplatelet activities depended upon enforcement of beta-turn structure or spacial rigidity of RGD sequences. The dose-dependent inhibitory effect on platelet aggregation induced by collagen showed that a ten-fold higher activity was found for a linear decapeptide, VVVRGDSVVV (V = Val), and a 100-fold increase for cyclic tetrapeptide, cyclo(RGDG), as compared with RGDS (half inhibition concentration, 0.1 mmol/L). Very potent antiplatelet agents, specially designed for the cardiopulmonary circulation, were successfully developed.