Preclinical development of the tsetse thrombin inhibitor

描述（由申请方提供）：血栓栓塞性疾病是发达国家发病率和死亡率的主要原因。尽管需要用于治疗和预防血栓形成的病理活化的有效疗法，但目前可用于静脉内肝素的替代品相对较少。抗血栓形成剂的总商业市场估计为每年20亿美元。从非洲锥虫（昏睡病）的昆虫载体Glossina morsitans morsitans的唾液中纯化并克隆了一种有效的凝血蛋白酶凝血酶小分子抑制剂。这种由32个氨基酸组成的多肽被命名为舌蝇凝血酶抑制剂（Tsetse Thrombin Inhibitor，TTI），是一种新型的凝血和凝血酶诱导的血小板聚集抑制剂。这个第一阶段STTR提案的长期目标是耶鲁大学和L2诊断公司之间的合作努力。New Haven，CT.，是生产毫克量的活性重组或合成TTI，其适合于未来临床开发作为治疗性抗血栓形成剂。重组TTI（rTTI）将在两种不同的真核系统中表达。将合成截短的TTI肽（sTTI），并使用凝血酶活性和离体全血凝固时间的体外测定以及凝血酶介导的血小板聚集测定将其与重组分子和全长抑制剂进行比较。最有前途的TTI肽将使用标准的体内血栓形成模型进一步表征。长期目标是开发重组或合成TTI作为治疗剂，用于治疗和预防与血栓形成激活相关的人类疾病，包括心血管疾病、中风和癌症

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