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Identification and characterization of novel antithrombotic PDI inhibitors

新型抗血栓 PDI 抑制剂的鉴定和表征

基本信息

批准号：
8401640
负责人：
Bruce Furie
金额：
$ 44.59万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8401640
关键词：
Antibodies Binding Binding Proteins Biological Assay Biological Availability Blood Clot Blood Platelets Blood coagulation Cell physiology Cells Characteristics Cytoplasmic Granules Deep Vein Thrombosis Development ERp57 Endothelial Cells Evaluation Fibrin Flavonoids Goals Hemostatic function Injury Instruction Integrins Isomerase Knowledge Laser injury Lasers Lead Mediating Modeling Modification Molecular Chaperones Mus Myocardial Infarction NMR Spectroscopy Oxidoreductase Permeability Plasma Platelet Activation Platelet aggregation Protein Disulfide Isomerase Pulmonary Embolism Role Rutin Site Solubility Stroke Structure-Activity Relationship Testing Thioredoxin Thromboembolism Thromboplastin Thrombosis Thrombus United States Venous base cytotoxicity dietary supplements endoplasmic reticulum glycoprotein p72 high throughput screening improved in vivo inhibitor/antagonist intravital microscopy mortality mouse model novel prevent small molecule therapy development

项目摘要

PROJECT SUMMARY (See instructions): Inhibition of protein disulfide isomerase (PDI) using antibodies prevents both platelet accumulation and fibrin formation in murine models of thrombus formation. This observation indicates that inhibition of PDI could represent a viable strategy for control of pathological thrombus formation. However, potent, selective small molecule inhibitors to test this hypothesis are not presently available. We have begun high throughput screening to identify compounds that inhibit PDI. A preliminary screen of ~5000 compounds identified PDI inhibitors with a hit rate of 0.3%. Among the active compounds were several flavonoids, including the widely used nutritional supplement quercetin-3-rutinoside. Quercetin-3-rutinoside was markedly antithrombotic in murine models. The fact that this PDI inhibitor is well-tolerated and potently antithrombotic in vivo supports the feasibility of inhibition of PDI for antithrombotic therapy. However, more selective, potent compounds with improved bioavailability are required. We will perform a large scale high throughput screen to identify novel PDI inhibitors. The objective of this project is to characterize a set of potent and selective PDI inhibitors as probes to study the role of PDI in thrombus formation and identify lead compounds that could be developed as antithrombotics. PDI demonstrates multiple functions in the vasculature including oxidoreductase/isomerase, chaperone, and denitrosation activities. In Aim 1, we will characterize PDI inhibitors on the basis of their ability to block these different activities. Studies performed in Aim 2 will use NMR spectroscopy to determine the structural basis of PDI inhibitor activity. The effect of PDI inhibitors on platelet activation and endothelial cell function will be detennined in Aim 3. Select compounds will then be tested for their inhibitory activity in a mouse model of thrombus formation using intravital microscopy (Aim 4). Evaluation of PDI inhibitors in enzymatic and cell-based assays will enable the identification of characteristics that are essential for the antithrombotic activity of PDI inhibitors. Such information will be critical for further development of PDI inhibitors as a novel class of antithrombotics.

项目概述（见说明）：