NOVEL ANTITHROMBOTIC AGENT

此SBIR申请是对第一阶段研究的资助申请，以 开发一种具有治疗用途的选择性抗血栓药。这个 将在本研究中开发的抗血栓药将通过 抑制凝血酶的形成。凝血酶是由 凝血酶原酶复合体的凝血酶原 Xa(一种丝氨酸蛋白酶)、因子Va(一种辅助因子)和钙离子聚集在一个 磷脂表面。本研究的基础是观察到 非蛋白水解型Xa因子(Xai因子)可引起 形成失活的凝血酶原酶复合体，限制凝血酶原酶的形成 凝血酶。这项第一阶段研究的具体目的是使用重组 人凝血因子Xa非蛋白水解型的表达技术 (RXai)，它将与人类组装中的活性因子Xa竞争 凝血酶原酶复合体。这项研究的第二阶段将针对测试 RXAI因子将抑制血栓形成的假说 选择一些具有良好特征的急性动脉动物模型 血栓形成。预计这项研究将导致 新型高效、高选择性抗血栓药物家族的开发 适用于治疗血栓形成的几种危及生命的药物 心血管疾病，如不稳定型心绞痛、心肌梗塞和 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.