The long-term objective of the proposed research is to develop an antithrombotic agent. Thrombus formation occurs in arteries when the glycoprotein IIb-IIIa complex on circulating platelets becomes activated, binds fibrinogen causing platelets to aggregate. Previous studies from the applicant's laboratory have 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 for Phase I of the present proposal is to identify the domain(s) within the fibrinogen molecule that bind to the platelet GPIIb-IIIa complex. Proteolytic fragments of fibrinogen will be analyzed for their ability to inhibit fibrinogen binding to GPIIb-IIIa. These peptides will then be isolated and tested for their abilities to directly bind GPIIb-IIIa and 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 site(s) of fibrinogen will be used to generate antithrombotic agents. This new class of drugs will be marketed commercially as agents that 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 occlusions.
| Walcott, G P; Melnick, S B; Chapman, F W et al. (1998) Relative efficacy of monophasic and biphasic waveforms for transthoracic defibrillation after short and long durations of ventricular fibrillation. Circulation 98:2210-5 |
