Research Project
3501728
The long-term objective of the proposed studies is the development of specific inhibitors of platelet aggregation as therapeutics in thrombooclusive cardiovascular disease. Platelet aggregation is in the initiating event in the formation of occlusive thrombi in the vasculature, and occurs when circulating platelets become activated and bind fibrinogen. There are no therapeutics available at this time that effectively inhibit the binding of bibrinogen to platelets, and limit thrombus formation. Phase I of the work will complete development of a solid-phase microtiter plate assay for the binding of fibrinogen to GPIIb-IIIa, and will identify the fibroingen-binding domains on GPIIIa will be tested for their ability to inhibit fribrinogen 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 of this proposal these peptides will be modified to optimize their affinity for fribrinogen 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 reocclusion after angioplasty.
