Prolonging Annexin Antithrombotic Activity

描述（由申请人提供）：需要开发一种可用于预防或治疗动脉或静脉血栓形成而不增加出血的药物。人胎盘抗凝蛋白膜联蛋白V通过结合活化血小板外表面的磷脂酰丝氨酸抑制凝血，其中磷脂不对称性丧失。重组人膜联蛋白V在实验动物模型中减少动脉和静脉血栓形成而不增加出血。然而，膜联蛋白V（32 kDa）迅速从循环进入尿，限制了其作为抗血栓剂的有用性。研究人员建议通过与聚乙二醇结合来增加膜联蛋白V的分子量。据预测，这种修饰将延长膜联蛋白V在循环中的半衰期及其抗凝活性，从而产生临床上有用的抗血栓形成剂。聚乙二醇化的膜联蛋白V也可以减轻再灌注损伤。研究者对I期的里程碑是开发一种具有显著延长的血清半衰期并保留其内在抗凝活性的聚乙二醇化膜联蛋白;血栓形成的临床疗效将在随后的SBIR-II期提案中进行测试。

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.