Preclinical development of the tsetse thrombin inhibitor

描述(申请人提供)：血栓栓塞性疾病是发达国家发病率和死亡率的主要原因。尽管需要有效的治疗方法来治疗和预防血栓形成的病理性激活，但目前可以替代静脉注射肝素的药物相对较少。抗血栓药物的商业市场总额估计为每年20亿美元。从非洲锥虫病(昏睡病)的昆虫媒介--血吸虫的唾液中纯化并克隆了一种有效的凝血酶小分子抑制物凝血酶。Tsetse凝血酶抑制物(TTI)是一种新型的凝血和凝血酶诱导的血小板聚集抑制物，由32个氨基酸组成。这项第一阶段STTR提案是耶鲁大学和康涅狄格州纽黑文的L 2诊断公司合作的结果，其长期目标是生产毫克数量的活性重组或合成TTI，作为一种治疗性抗血栓药物用于未来的临床开发。重组TTI(RTTI)将在两种不同的真核系统中表达。将合成截短型TTI多肽(STTI)，并与重组分子和全长抑制物进行体外凝血酶活性和体外全血凝血时间的比较，以及凝血酶介导的血小板聚集试验。最有希望的TTI多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的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