Preclinical development of the tsetse thrombin inhibitor

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DESCRIPTION (provided by applicant): Thromboembolic disease is a major cause of morbidity and mortality in the developed world. Despite the need for effective therapies for treating and preventing pathologic activation of thrombosis, there are relatively few currently available alternatives to intravenous heparin. The total commercial market for antithrombotic agents has been estimated at 2 billion dollars per year. A potent small molecule inhibitor of the coagulation protease thrombin has been purified and cloned from the saliva of Glossina morsitans morsitans, the insect vector of African trypanosomiasis (sleeping sickness). This 32 amino acid peptide, named Tsetse Thrombin Inhibitor (TTI), is a novel inhibitor of coagulation and thrombin induced platelet aggregation. The long-term objective of this Phase I STTR proposal, which represents a collaborative effort between Yale University and L 2 Diagnostics, Inc. of New Haven, CT., is to produce milligram quantifies of active recombinant or synthetic TTI suitable for future clinical development as a therapeutic anti-thrombotic agent. Recombinant TTI (rTTI) will be expressed in two distinct eukaryotic systems. Truncated TTI peptides (sTTI) will be synthesized and compared to the recombinant molecules and the full length inhibitor using in vitro assays of thrombin activity and ex vivo whole blood clotting times, as well as thrombin mediated platelet aggregation assays. The most promising TTI peptides will be further characterized using standard in vivo models of thrombosis. The long-term objective is to develop recombinant or synthetic TTI as a therapeutic agent for the treatment and prevention of human diseases associated with activation of thrombosis, including cardiovascular disease, stroke, and cancer