Modulation of the activity and assessment of the receptor selectivity in a series of new RGD-containing peptides

We have investigated the structure-activity relationship of a series of new synthetic RGD analogs and their potential use as specific platelet aggregation inhibitors. Twelve short linear peptides showed high potency to inhibit aggregation in ADP-stimulated dog platelets. In order to assess the selectivity of these analogs towards platelet integrin GPIIb-IIIa, a new cell adhesioninhibition system was devised which was able to discriminate between the two closely related β3-integrins of the vasculature, GPIIb-IIIa(αIIbβ3), present in platelets, and the vitronectinreceptor (αvβ3), expressed in endothelial cells and platelets. As reported for other peptides by Scarborough et. al. (1993, J. Biol. Chem. 268, 1066), the analogs containing lysine instead of arginine in position 1 showed increased selectivity towards GPIIb-IIIa. One of them, in which the piperidine carboxylic group was attached to the N-terminus of KGDW, not only strongly inhibited platelet aggregation, but also selectively abolished cell adhesionmediated by GPIIb-IIIawithout effect on the vitronectinreceptor.