DEVELOPMENT OF ANTITHROMBOTIC AGENTS

THE LONG-TERM OBJECTIVE OF THIS RESEARCH IS TO DEVELOP AN ANTITHROMBOTIC AGENT. THROMBUS FORMATION OCCURS IN ARTERIESWHEN THE GLYCOPROTEIN (GP) IIB-IIIA COMPLEX ON CIRCULATING PLATELETS BECOMES ACTIVATED AND BINDS FIBRINOGEN, CAUSING PLATELETS TO AGGREGATE. PREVIOUS STUDIES CHARACTERIZED THE STRUCTURE OF GPIIB-IIIA, CLONED THE CDNA ENCODING GPIIIA, AND DEVELOPED FIBRINOGEN-BINDING ASSAYS FOR THE PURIFIED GPIIB-IIIA COMPLEX. THE SPECIFIC AIM OF PHASE I IS TO IDENTIFY THE DOMAINS WITHIN THE FIBRINOGEN MOLECULE THAT BIND TO THE PLATELET GPIIB-IIIA COMPLEX. PROTEOLYTIC FRAGMENTS OF FIBRINOGEN WILL BE ANALYZED FOR THEIR ABILITY TO INHIBIT PLATELET AGGREGATION. INHIBITORY PEPTIDES GENERATED BY SEVERAL PROTEASES WILL BE PRODUCED SO THAT OVERLAPPING SEQUENCES CONTAINING THE ACTIVE SITE CAN BE IDENTIFIED. IN PHASE II OF THIS STUDY, SEQUENCES OF THE ACTIVE SITES OF FIBRINOGEN WILL BE USED TO GENERATE ANTITHROMBOTIC AGENTS. THIS NEW CLASS OF DRUGS WILL LIMIT THROMBUS FORMATION IN A VARIETY OF CLINICAL SITUATIONS, INCLUDING UNSTABLE ANGINA, THROMBOTIC STROKE, PATIENTS UNDERGOING ANGIOPLASTY AND FIBRINOLYSIS, AND PATIENTS AT RISK FOR CORONARY OCCLUSION.