ARG-GLY-ASP PEPTIDE INHIBITORS OF PLATELET AGGREGATION

THE INCIDENCE OF MYOCARDIAL INFARCTION IS RELATED TO THE EXTENT TO WHICH ARTERIES ARE OCCLUDED BY BLOOD CLOTS (THROMBI). PLATELETS, CELLS THAT AGGREGATE IN RESPONSE TO ARTERIAL INJURY, ARE THE MAJOR CELLULAR COMPONENTS FOUND IN SUCH THROMBI. THROMBOLYTIC THERAPIES, WHICH DO NOT AFFECT PLATELETS, ARE EFFECTIVE IN REMOVING CLOTS BUT DO NOT PREVENT PLATELET-DEPENDENT REOCCLUSION AND CAN CAUSE HEMORRHAGE, WHICH REQUIRES PLATELET ADHESION. PLATELET AGGREGATION IS MEDIATED BY CELL SURFACE GLYCOPROTEIN (GP) IIB/IIIA COMPLEX, WHICH RECOGNIZES THE ARG-GLY-ASP (RGD) SEQUENCE FOUND IN PLASMA ADHESIVE PROTEINS SUCH AS FIBRINOGEN AND VON WILLEBRAND FACTOR. RGD-CONTAINING PEPTIDE ANALOGS WILL BE SCREENED FOR THEIR SUPERIOR INHIBITORY EFFECTS AGAINST PLATELET AGGREGATION AS WELL AS FOR INCREASED SPECIFICITY FOR THE GP IIB/IIIA RECEPTOR. ALSO, THE RGD-DEPENDENT INTERACTIONS OF GP IIB/IIIA WITH MAJOR ADHESIVE PROTEINS WILL BE ASSESSED VIA THE ATTACHMENT OF LIPOSOMES CONTAINING THE PURIFIED RECEPTOR. PEPTIDES EXHIBITING HIGH ANTAGONISTIC POTENCIES AGAINST THESE RESPONSES WILL ALSO BE TESTED FOR THEIR UNDESIRABLE EFFECTS ON THE RELEASE OF VASOCONSTRICTORY AND CHEMOTACTIC SUBSTANCES FROM PLATELETS AND ON ENDOTHELIAL CELL ACTIVATIONAND DETACHMENT. FINALLY, THE ANTITHROMBOTIC EFFICACIES OF CANDIDATE PEPTIDES WILL BE DETERMINED IN SEVERAL ANIMAL MODELS OF THROMBOSIS. IT IS HOPED THAT THIS RESEARCH WILL LEAD TO A PRODUCT WITH ACTIONS SYNERGISTIC TO THOSE OF CONVENTIONAL THROMBOLYTIC THERAPIES.