A novel platelet inhibitor from bloodfeeding hookworms

一种来自吸血钩虫的新型血小板抑制剂

• 批准号: 6582953
• 负责人: MICHAEL CAPPELLO
• 金额: $ 9.94万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-18 至 2004-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6582953
• 关键词: Escherichia coli; Nematoda; SDS polyacrylamide gel electrophoresis; anticoagulants; binding sites; blood coagulation; cell surface receptors; collagen; fibrinogen; glycoproteins; high performance liquid chromatography; integrins; mass spectrometry; platelet aggregation inhibitors; platelets; protein purification; recombinant proteins; technology /technique development; thromboembolism; thrombosis

DESCRIPTION (provided by applicant): Thromboembolic disease is a major cause of morbidity and mortality in the developed world. Because platelets play a critical role in the activation and propagation of thrombosis, they represent important targets for new anti-thrombotic drugs. A potent inhibitor of human platelet function has been isolated from the bloodfeeding hookworm, Ancylostoma caninum. This novel protein is the first naturally occurring compound shown to block the binding of platelet integrins GPIIb/IIIa and GPIa/IIa, the cell surface receptors for fibrinogen and collagen, respectively. The objective of this Phase I STTR grant application is to purify milligram quantities of active recombinant hookworm platelet inhibitor (rHPI) suitable for testing in vivo and in vitro. The rHPI will be characterized using whole platelet assays of aggregation and adhesion. In addition, quantitative experiments will measure the ability of rHPI to block the interaction of collagen and fibrinogen with their respective integrin receptors. Competition experiments with various peptides will delineate HPI binding sites and further characterize its molecular mechanism of action. Lastly, truncated variants of rHPI will be produced in order to determine the smallest protein domain with preserved antiplatelet activity. The long-term objective is to develop rHPI as a therapeutic agent for the treatment of thrombotic disorders in humans.

描述（由申请人提供）：血栓栓塞性疾病是发达国家发病和死亡的主要原因。 由于血小板在血栓形成的激活和传播中发挥着关键作用，因此它们代表了新型抗血栓药物的重要靶点。 人类血小板功能的有效抑制剂已从吸血钩虫犬钩虫中分离出来。 这种新型蛋白质是第一种天然存在的化合物，可阻断血小板整合素 GPIIb/IIIa 和 GPIa/IIa（分别是纤维蛋白原和胶原蛋白的细胞表面受体）的结合。 此一期 STTR 拨款申请的目的是纯化毫克量的活性重组钩虫血小板抑制剂 (rHPI)，适合体内和体外测试。 rHPI 将使用全血小板聚集和粘附测定进行表征。 此外，定量实验将测量 rHPI 阻断胶原蛋白和纤维蛋白原与其各自的整联蛋白受体相互作用的能力。 各种肽的竞争实验将描绘 HPI 结合位点并进一步表征其作用的分子机制。 最后，将产生 rHPI 的截短变体，以确定保留抗血小板活性的最小蛋白质结构域。 长期目标是开发 rHPI 作为治疗人类血栓性疾病的治疗剂。