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Thrombin-PAR inhibitors
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Fernanda Marques
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The proteolytic enzyme alpha-thrombin is a key catalyst for both platelet aggregation and the formation of fibrin clots. During a heart attack the coronary vessels are further occluded due to thrombin activated platelet aggregation. Potent thrombin inhibitors are available that can reduce the damage due to a heart attack by limiting the degree of platelet aggregation and thereby keeping the coronary vessels open. However, these inhibitors also interfere with normal thrombin catalyzed fibrin clot formation, which can lead to intracerebral hemorrhage. The goal of this project is to improve the activity of agents that interfere with the interaction between thrombin and platelets but that do not interfere with thrombin mediated fibrin clotting. Our project involves the design and synthesis of selective inhibitors, termed thrombostatins, that prevent interaction of α-thrombin with protease-activated GPCRs PAR1 and PAR4 and does not interfere with alpha-thrombin cleaving of other substrates.
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Collaborators Involved
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Alvin H. Schmaier
, MD Professor of Pathology Director of the Coagulation Laboratory Department of Pathology Medical School UofM
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Related Publications
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Burke FM, Warnock M, Schmaier AH, Mosberg HI
Synthesis of novel peptide inhibitors of thrombin-induced platelet activation
Chem. Biol. Drug. Des., 68: 235-258 (2006)
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External Funding
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A. Hasan, PI
Michigan Life Sciences Corridor Fund
Thrombostatin. A Novel Anti-Platelet Agent
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R42 HL61981 A. Hasan, PI
NIH/NHLBI&Thromgen, Inc.
Thrombostatin in the Folts Model for Coronary Thrombosis
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