PEPTIDE INHIBITORS OF PLATELET AGGREGATION

THE LONG-TERM OBJECTIVE OF THIS RESEARCH IS THE DEVELOPMENT OF SPECIFIC INHIBITORS OF PLATELET AGGREGATION AS THERAPEUTICS IN THROMBO-OCCLUSIVE CARDIOVASCULAR DISEASE. PLATELET AGGREGATION IS THE INITIATING EVENT IN THE FORMATION OF OCCLUSIVE THROMBI IN THE VASCULATURE AND OCCURSWHEN CIRCULATING PLATELETS BECOME ACTIVATED AND BIND FIBRINOGEN. THERE ARE NO THERAPEUTICS AVAILABLE AT THIS TIME THAT EFFECTIVELY INHIBIT THE BINDING OF FIBRINOGEN TO PLATELETS AND LIMIT THROMBUS FORMATION. PHASE I WORK WILL COMPLETE DEVELOPMENT OF A SOLID-PHASE MICROTITER PLATE ASSAY FOR THE BINDING OF FIBRINOGEN TO GPIIB-IIIA AND WILL IDENTIFY THE FIBRINOGEN-BINDING DOMAINS ON GPIIB-IIIA. OVERLAPPING SYNTHETIC PEPTIDES FROM GPIIB AND GPIIIA WILL BE TESTED FOR THEIR ABILITY TO INHIBIT FIBRINOGEN BINDING TO GPIIB-IIIA. CANDIDATE PEPTIDES WILL THEN BE TESTED FOR THEIR ABILITY TO INHIBIT THE BINDING OF (125)I-FIBRINOGEN TO ACTIVATED PLATELETS AND TO INHIBIT PLATELET AGGREGATION. IN PHASE II, THESE PEPTIDES WILL BE MODIFIED TO OPTIMIZE THEIR AFFINITY FOR FIBRINOGEN AND IN VIVO PHARMACOKINETICS. IDENTIFICATION OF THE FIBRINOGEN-BINDING DOMAINS ON GPIIB-IIIA WILL THUS FORM THE BASIS FOR THE RATIONAL DESIGN OF INHIBITORS OF FIBRINOGEN BINDING TO THIS RECEPTOR. THE THERAPEUTICS DEVELOPED FROM THIS APPROACH WILL BE USED IN A WIDE RANGE OF CLINICAL SITUATIONS CHARACTERIZED BY THROMBOSIS, SUCH AS UNSTABLE ANGINA, STROKE, AND REOCCLUSIONAFTER ANGIOPLASTY.