Prolonging Annexin Antithrombotic Activity

延长膜联蛋白抗血栓活性

• 批准号: 6643783
• 负责人: HOWARD SCHULMAN
• 金额: $ 9.27万
• 依托单位: SURROMED, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-29 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6643783
• 关键词: annexins; anticoagulants; blood circulation; blood coagulation; chemical conjugate; drug design /synthesis /production; hemorrhage; laboratory mouse; laboratory rabbit; method development; molecular weight; pharmacokinetics; platelets; polyethylene glycols; protein binding; protein purification; prothrombin time; recombinant proteins; thromboplastin; thrombosis

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.

描述（由申请人提供）：需要开发可用于预防或治疗动脉或静脉血栓形成的药物而不会增加出血。人胎盘抗凝蛋白膜联蛋白V通过与磷脂血小板外表面上的磷脂酰丝氨酸结合而抑制凝血，在该血小板的外表面失去了磷脂不对称。重组人膜联蛋白V在实验动物模型中降低动脉和静脉血栓形成而不会增加出血。然而，膜联蛋白V（32 kDa）迅速从循环中传递到尿液中，限制了其作为抗心含量剂的有用性。研究人员建议通过与聚乙烯乙二醇结合来增加膜联蛋白V的分子量。据预测，这种修饰将延长循环中膜联蛋白V的半衰期及其抗凝活性，从而产生临床上有用的抗直血栓药物。 Pegypet Annexin V也可能减弱再灌注损伤。研究人员的第一阶段里程碑是具有明显延长血清半衰期的卵胶的膜联蛋白的发展，并保留其内在的抗凝活性。血栓形成的临床功效将在随后的SBIR-Shase II建议中进行测试。