Protein disulfide isomerases: A new class of antithrombotic targets

蛋白质二硫键异构酶：一类新的抗血栓靶点

• 批准号: 8656766
• 负责人: Bruce Furie
• 金额: $ 224.71万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656766
• 关键词: Address; Animals; Anticoagulants; Antiphospholipid Syndrome; Ascorbic Acid; Award; Binding Proteins; Center for Translational Science Activities; Clinical; Data; Deep Vein Thrombosis; Development; Disease; Drug Industry; Drug Kinetics; Effectiveness; Electron Transport Pathway; Evaluation; Event; Fibrinolytic Agents; Funding; Generations; Goals; Grant; Hemostatic Agents; Heparin; Human; Institutes; Intellectual Property; Isomerase; Knowledge; Laboratories; Laboratory Finding; Lead; Ligands; Malignant Neoplasms; Modeling; Molecular Biology; Mus; Myocardial Infarction; NMR Spectroscopy; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Property; Protein Disulfide Isomerase; Public Health; Pulmonary Embolism; Quercetin; Research; Resources; Role; Rutin; Stroke; Structure; Sulfhydryl Compounds; Testing; Therapeutic Agents; Thrombocytopenia; Thromboembolism; Thrombosis; Thrombus; Translating; United States; United States National Institutes of Health; Venous; Work; abstracting; design; drug development; in vivo; inhibitor/antagonist; interest; intravital microscopy; mortality; multidisciplinary; novel; prevent; programs; skills; small molecule; structural biology

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.

描述（由申请人提供）： 血栓和止血疾病转化研究中心的这份申请描述了开发一类新型抗血栓药物的研究。组成项目探索蛋白质二硫键异构酶(PD1)作为抗血栓靶点，使用异槲皮素、槲皮素3-芸香苷和槲皮素作为PD1抑制剂。在项目#1中，Bruce Furie博士与Barbara Furie博士和Mingdong Huang博士一起探索PD1参与血栓形成的机制，并将在体内血栓模型中测试PD1抑制剂是否可以预防小鼠血栓形成。黄博士将解析具有和不具有结合的PD1抑制剂的PD1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PD1抑制剂。 PD1结构域将被表达并通过NMR波谱检查它们与小分子PD1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型抗血栓药的PD1配体的数量。在项目 #3 中，Jeffrey Zwicker 博士与 Donna Neuberg 博士将探索槲皮素和异槲皮素在人类中的抗血栓特性，这些药物已被批准供人类使用。将在存在和不存在抗坏血酸的情况下对槲皮素和异槲皮素进行药代动力学研究，以确定最佳递送。将评估PD1抑制剂在三项单独的人类研究中的有效性：癌症患者的血栓栓塞事件；肝素诱导的血小板减少症和血栓形成；抗磷脂综合征。该 TRC-THD 将包括四个核心，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。活体显微镜检查和动物核心（核心 B）将由 Barbara C. Furie 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 Natalia Beglova 博士共同指导。转化技能发展核心（核心 D）将由 Kenneth Bauer 博士指导。该中心将致力于开发一类针对PD1的新型抗血栓药物，具有抗血小板和抗凝血特性。