NOVEL ANTITHROMBOTIC AGENT

本SBIR申请是一项I期研究的资金申请， 开发具有治疗用途的选择性抗血栓剂。 的 本研究中开发的抗血栓药物将通过以下方式发挥作用： 抑制凝血酶的形成。 凝血酶是由 酶原凝血酶原由凝血酶原酶复合物组成， Xa（丝氨酸蛋白酶）、因子Va（辅因子）和Ca2+组装在一个细胞上， 磷脂表面 本研究报告的依据是以下观察结果： Xa因子（Xai因子）的蛋白水解无活性形式导致 形成无活性的凝血酶原酶复合物，并限制 凝血酶 本I期研究的具体目的是使用重组 表达蛋白水解无活性形式人因子Xa的技术 （rXai），其将在人类细胞的组装中与活性因子Xa竞争。 凝血酶原酶复合物 本研究的第二阶段将用于测试 假设因子rXai将抑制血栓形成， 选择数量充分表征的急性动脉炎动物模型 血栓形成 预计这项研究将导致 开发一个新的强效和高选择性抗血栓形成药物家族 适用于治疗几种危及生命的血栓形成的药物 心血管疾病，如不稳定型心绞痛、心肌梗死和 血栓性中风

This SBIR application is a request for funding of a Phase I study to develop a selective antithrombotic with therapeutic usefulness. The antithrombotic to be developed in the present study will function by inhibiting the formation of thrombin. Thrombin is generated from the zymogen prothrombin by the prothrombinase complex which consists of factor Xa (a serine protease), factor Va (a co-factor) and Ca2+ assembled on a phospholipid surface. The present study is based on the observation that proteolytically inactive forms of factor Xa (factor Xai) cause the formation of inactive prothrombinase complexes and limit the formation of thrombin. The specific aim of this Phase I study is to use recombinant technology to express a proteolytically inactive from of human factor Xa (rXai) which will compete fro active factor Xa in the assembly of the human prothrombinase complex. Phase II of this study will be directed to testing the hypothesis that factor rXai will inhibit the formation of thrombi in a select number of well characterized animal models for acute arterial thrombosis. It is anticipated that this research will lead to the development of a new family of potent and highly selective antithrombotic drugs suitable for the treatment of thrombosis in several life-threatening cardiovascular diseases such as unstable angina, myocardial infarction and thrombotic stroke.