Prolonging Annexin Antithrombotic Activity

描述(由申请人提供)：需要开发一种能够在不增加出血的情况下预防或治疗动脉或静脉血栓形成的试剂。人胎盘抗凝蛋白Annexin V通过与活化的血小板外表面的磷脂酰丝氨酸结合来抑制凝血，在活化的血小板上磷脂不对称消失。重组人膜联蛋白V在不增加出血的情况下减少实验动物模型中的动脉和静脉血栓形成。然而，膜联蛋白V(32 KDa)迅速从循环进入尿液，限制了其作为抗血栓药的有效性。研究人员建议通过与聚乙二醇偶联物来增加膜联蛋白V的分子量。据预测，这种修饰将延长Annexin V在循环中的半衰期，并延长其抗凝血活性，从而生产出一种临床上有用的抗血栓药物。聚乙二醇化的膜联蛋白V也可减轻再灌注损伤。研究人员第一阶段的里程碑是开发一种聚乙二醇化的膜联蛋白，具有显著延长的血清半衰期，并保持其固有的抗凝血活性；血栓形成的临床疗效将在随后的SBIR第二阶段提案中进行测试。

DESCRIPTION (provided by applicant): There is need to develop an agent that can be used to prevent or treat arterial or venous thrombosis without increasing hemorrhage. The human placental anticoagulant protein annexin V inhibits coagulation by binding to phosphatidylserine on the outer surface of activated platelets in which phospholipid asymmetry is lost. Recombinant human annexin V decreases arterial and venous thrombosis in experimental animal models without increasing hemorrhage. However, annexin V (32 kDa) rapidly passes from the circulation into the urine limiting its usefulness as an anti-thromobic agent. The investigators propose to increase the molecular weight of annexin V by conjugation with polyethylene glycol. It is predicted that this modification will prolong the half-life of annexin V in the circulation and its anticoagulant activity, thereby producing a clinically useful anti-thrombotic agent. Pegylated annexin V may also attenuate reperfusion injury. The investigators' milestone for Phase I is development of a pegylated annexin with significantly prolonged serum half-life and which retains its intrinsic anticoagulant activity; clinical efficacy in thrombosis will be tested in a subsequent SBIR-Phase II proposal.