BPTI-MUTANTS AS NOVEL ANTITHROMBOTIC AGENTS

心血管疾病是死亡和发病的主要原因， 工业化世界。 血栓形成是由激活 血液凝固级联反应是导致 包括这种疾病的三个主要类别，包括：冠状动脉 动脉疾病导致急性心肌梗死（AMI）， 脑血管疾病导致中风和静脉血栓形成， 经常导致肺栓塞 只有数量有限的 治疗这些疾病的方法， 非常有效。 我们在第二阶段建议中提议， 选择性凝血抑制剂的改进和评价 因子VIIa和Xa成功地从a 原型Kunitz丝氨酸蛋白酶抑制剂的I期部分， 补助金 这些研究将包括现场定向和随机 诱变以提高抑制剂的效力和选择性 基于酶的三维结构测定 抑制剂复合物和完整的体外和体内评价， 选择的抑制特性和抗血栓形成有效性 抑制剂在建立的血栓形成实验性整体动物模型中的应用。 预计一种新的和更临床有效的 抗血栓形成治疗将作为这些研究的结果出现。

Cardiovascular disease is the major cause of mortality and morbidity in the industrialized world. Thrombosis resulting from the activation of the blood coagulation cascade is the common etiology which underlies the three main categories that comprise this disease which includes: coronary artery disease leading to acute myocardial infarction (AMI), cerebrovascular disease leading to stroke and venous thrombosis which often leads to pulmonary embolism. There are only a limited number of therapies available to treat these diseases none of which are overwhelmingly effective. We propose in this phase II proposal to improve upon and evaluate the selective inhibitors of blood coagulation factors VIIa and Xa successfully engineered from mutants of a prototypical Kunitz serine protease inhibitor in the phase I portion of the grant. These studies will include site directed and random mutagenesis to improve the potency and selectivity of the inhibitors based on the three dimensional structural determination of an enzyme inhibitor complex and the full in vitro and in vivo evaluation of the inhibitory properties and antithrombotic effectiveness of selected inhibitors in established experimental whole animal models of thrombosis. It is anticipated that a novel and more clinically effective antithrombotic treatment will emerge as a result of these studies.