Protein disulfide isomerases: A new class of antithrombotic targets

描述(由申请人提供)： 血栓和止血疾病翻译研究中心的这项申请描述了开发一类新型抗血栓药物的研究。组份项目探索蛋白质二硫键异构酶(PDL)作为抗血栓靶点，使用异槲皮素、槲皮素3-芦丁糖苷和槲皮素作为PDL的抑制剂。在项目1中，Bruce Furie博士与Barbara Furie博士和黄明东博士一起探索PDL参与血栓形成的机制，并将在体内测试PDL抑制剂是否可以防止小鼠血栓形成。黄博士将解决在有和没有结合的PDL抑制剂的情况下PDL的晶体结构。在项目2中，Robert Flaumenhaft博士和Natalia Beglova博士将在布罗德研究所寻找更有效的PDL抑制剂。将表达PDL结构域，并用核磁共振波谱检测它们与小分子PDL抑制剂的相互作用。新的配体将由布罗德研究所的化学家设计、合成并随后进行测试。该项目将扩大可用于评估这类新的抗血栓药物的PDL配体的数量。在项目3中，Jeffrey Zwicker博士和Donna Neuberg博士将探索被批准用于人类使用的槲皮素和异槲皮素在人体内的抗血栓特性。在抗坏血酸存在和不存在的情况下，将进行槲皮素和异槲皮素的药代动力学研究，以确定最佳给药方案。PDL抑制剂的有效性将在三个不同的人类研究中进行评估：癌症患者的血栓栓塞事件；肝素诱导的血小板减少和血栓形成；抗磷脂综合征。这一TRC-THD将包括四个核心，将为整个计划提供支持。行政核心(核心A)将由Bruce Furie博士领导，并将协调三个项目的活动。活体显微镜和动物核心(核心B)将由芭芭拉·C·弗里博士指导。分子和结构生物学核心(核心C)将由黄明东博士和娜塔莉亚·贝格洛娃博士共同执导。翻译技能发展核心(核心D)将由肯尼斯·鲍尔博士指导。该中心将致力于开发一类新的针对PDL的抗血栓药物，具有抗血小板和抗凝特性。

DESCRIPTION (provided by applicant): This application for a Translational Research Center in Thrombotic and Hemostatic Disorders describes research to develop a novel class of antithrombotic agents. Component projects explore protein disulfide isomerase (PDl) as an antithrombotic target using isoquercetin, quercetin 3-rutinoside and quercetin as inhibitors of PDl. In Project #1, Dr. Bruce Furie, with Dr. Barbara Furie and Dr. Mingdong Huang, explore the mechanism by which PDl participates in thrombus generation and will test in vivo thrombosis models whether PDl inhibitor can prevent thrombosis in mice. Dr. Huang will solve the crystal structure of PDl with and without a bound PDl inhibitor. In Project #2, Dr. Robert Flaumenhaft and Dr. Natalia Beglova will search for more potent PDl inhibitors at the Broad Institute. PDl domains will be expressed and their interaction with small molecule PDl inhibitors examined by NMR spectroscopy. New ligands will be designed, synthesized by chemists at the Broad Institute and subsequently tested. This project will expand the number of PDl ligands available for evaluation in this new class of antithrombotics. In Project #3, Dr. Jeffrey Zwicker, with Dr. Donna Neuberg, will explore the antithrombotic properties of quercetin and isoquercetin in humans, agents approved for human use. A pharmacokinetic study with quercetin and isoquercetin in the presence and absence of ascorbic acid will be performed to determine optimal delivery. The effectiveness of the PDl inhibitor in three separate human studies will be evaluated: thromboembolic events in patients with cancer; heparin-induced thrombocytopenia and thrombosis; anti-phospholipid syndrome. This TRC-THD will include four cores that will provide support to the overall program. The Administrative Core (Core A) will be directed by Dr. Bruce Furie, and will coordinate the activities of the three projects. The Intravital Microscopy and Animal Core (Core B) will be directed by Dr. Barbara C. Furie. The Molecular and Structural Biology core (Core C) will be co-directed by Dr. Mingdong Huang and Dr. Natalia Beglova. The Translational Skills Development Core (Core D) will be directed by Dr. Kenneth Bauer. The Center will work to develop a new class of antithrombotic agents directed against PDl with both antiplatelet and anticoagulant properties.