Preclinical development of the tsetse thrombin inhibitor

采采蝇凝血酶抑制剂的临床前开发

• 批准号: 6789237
• 负责人: MICHAEL CAPPELLO
• 金额: $ 9.82万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-07 至 2005-06-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6789237
• 关键词: Glossinidae; anticoagulants; biological products; biotechnology; drug design /synthesis /production; enzyme inhibitors; laboratory rat; peptide chemical synthesis; platelet aggregation inhibitors; recombinant proteins; small molecule; thrombin; thromboembolism; thrombosis

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

描述（由申请人提供）：血栓栓塞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和预防血栓形成病理激活的疗法，但目前几乎没有静脉内肝素的可用替代方法。抗血栓药物的总商业市场估计为每年20亿美元。凝结蛋白酶凝血酶的有效的小分子抑制剂已被纯化并从Glossina Morsitans Morsitans的唾液中克隆，这是非洲锥虫病的昆虫媒介（睡眠疾病）。这种32个氨基酸肽，称为TSETSE凝血酶抑制剂（TTI），是一种新型的凝结抑制剂，凝血酶诱导的血小板聚集。 I阶段ISTTR提案的长期目标，代表了耶鲁大学与康涅狄格州纽黑文市的L 2 Diagnostics，Inc。之间的协作努力，是生产适合未来临床开发的主动重组或合成TTI的毫克量化作为治疗性抗脉止药。重组TTI（RTTI）将在两个不同的真核系统中表达。使用凝血酶活性的体外测定法和体内全血液凝结时间，以及凝血酶介导的血小板聚集测定，将合成截短的TTI肽（STTI），并与重组分子和全长抑制剂合成并进行比较。使用标准的体内血栓形成模型，最有希望的TTI肽将进一步表征。长期目标是将重组或合成TTI作为治疗和预防与血栓激活相关的人类疾病的治疗剂，包括心血管疾病，中风和癌症