NOVEL ANTITHROMBOTIC AGENT

此SBIR申请是对第二阶段研究的资助申请，以 开发一种治疗有效的抗血栓药物。这个 将在本研究中开发的抗血栓药物的作用是 抑制凝血酶的形成。 凝血酶是一种强有力的促血栓激动剂，来源于凝血酶原 凝血酶原酶复合体的催化活性。情结 由Xa因子(丝氨酸蛋白酶)、Va因子(辅助因子)和钙离子组成 组装在磷脂表面。复数关联因子Xa是 负责激活凝血酶的生理酶。 在第一阶段的研究中，我们表达并鉴定了一种蛋白水解物 人凝血因子Xa的非活性形式(RXAI)。RXAI因子抑制血管内皮细胞生长 凝血酶原酶替代血浆凝血因子Xa形成凝血酶 很复杂。因子rxai代表了一类新的抗凝血剂 通过直接干扰凝血复合体的形成发挥作用。阶段 这项研究的第二部分将致力于扩大该产品的生产 重组蛋白及rXAI抗血栓活性的检测 在兔和狒狒动物血栓形成模型中。本研究的第三阶段 将适用于获得联邦药品和管理局调查 新药(IND)批准状态，并正在进行人体临床试验 RXAI因子的疗效。预计这项研究将会得到发展 一种高效、高选择性的抗血栓药，适用于 几种危及生命的心血管疾病血栓形成的治疗 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.