Peptidomimetic Inhibitors of Platelet Adhesion as Potential Novel Antiplatelet Agents

摘要

There is currently no agent in clinical use that prevents thrombosis by targeting its earliest upstream event, i.e. platelet adhesion. This occurs through the interactions of the platelet-receptor, glycoprotein Ib alpha (GPIb alpha), with its immobilized ligand Willebrand factor (vWF). These interactions take place in response to vessel injury or are induced by shear stress in occluded arteries. The crystal structure of the GPIb alpha-vWF complex has been reported recently and showed that the interaction surface encompasses two distinct areas and is extended, making this interface a difficult target for small ("drug-like") molecules. The two epitopes of GPlb, (Cys~4-Cys~(17)) and (Asp~(235)-Ser~(241)), in contact with vWF, form a 14-residue and a 16-residue P-hairpin, respectively. We have therefore prepared beta-hairpin peptidomimetics modeled on these surface portions of GPIba, by cyclizing 12 to 16 residues from the protein sequence onto a beta-turn stabilizing motif. The ability of these mimetics to disrupt GPIb alpha-vWF interactions was evaluated in vitro. The results obtained with the beta-hairpin mimetics based on the epitope Asp~(235)-Ser~(241) are presented here.