NOVEL ANTITHROMBOTIC AGENT

本SBIR申请是一项II期研究的资金申请， 开发治疗有效的抗血栓剂。 的 在本研究中开发的抗血栓形成剂的功能是 抑制凝血酶的形成。 凝血酶是一种有效的促血栓形成激动剂，来源于凝血酶原 凝血酶原酶复合物的催化活性。 复杂 由因子Xa（丝氨酸蛋白酶）、因子Va（辅因子）和Ca 2+组成 组装在磷脂表面上。 复合相关因子Xa是 负责激活凝血酶的生理酶。 在I期研究中，我们表达并表征了一种蛋白水解的 人因子Xa（rXai）的失活形式。 因子rXai抑制 通过替换凝血酶原酶中的血浆因子Xa形成凝血酶 复杂. 因子rXai代表一类新的抗凝剂， 通过直接干扰凝血复合物的形成而发挥作用。 相 本研究的第二部分将致力于扩大这种 重组蛋白和检测因子rXai的抗血栓活性 在兔和狒狒动物血栓形成模型中。 本研究的III期 将适用于获得联邦药品和行政管理局认证 新药（IND）批准状态，并进行人体临床试验 因子rXai的功效。 预计这项研究将发展 一种有效的和高选择性的抗血栓形成剂， 治疗几种危及生命的心血管血栓 疾病

This SBIR application is a request for funding of a Phase II study to develop a therapeutically effective antithrombotic agent. The antithrombotic agent to be developed in the present study functions by inhibiting the formation of thrombin. Thrombin is a potent thrombogenic agonist and is derived from prothrombin by the catalytic activity of the prothrombinase complex. The complex consists of factor Xa (a serine protease), factor Va (a co-factor) and Ca2+ assembled on phospholipid surfaces. Complex associated factor Xa is the physiologic enzyme responsible for the activation of thrombin. In the Phase I study we expressed and characterized a proteolytically inactive form of human factor Xa (rXai). Factor rXai inhibits the formation of thrombin by replacing plasma factor Xa in the prothrombinase complex. Factor rXai represents a new class of anticoagulants which function by direct interference with coagulation complex formation. Phase II of this study will be directed to scaling up production of this recombinant protein and testing the antithrombotic activity of factor rXai in rabbit and baboon animal thrombosis models. Phase III of this study will be applied to obtaining Federal Drug and Administration investigatory new drug (IND) approval status, and proceeding to test the human clinical efficacy of factor rXai. It is anticipated that this research will develop a potent and highly selective antithrombotic agent suitable for the treatment of thrombosis in several life-threatening cardiovascular diseases.