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Identification of an inhibitor of PDI-GPIbalpha signaling as a novel antithromboinflammatory agent

鉴定 PDI-GPIbalpha 信号传导抑制剂作为新型抗血栓炎症剂

基本信息

批准号：
10242945
负责人：
Jaehyung Cho
金额：
$ 55.13万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-04 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242945
关键词：
Affect Animal Model Animals Anti-Inflammatory Agents Antibodies Asia Back Binding Bleeding time procedure Blocking Antibodies Blood Platelets Blood Vessels Blood flow Canis familiaris Cardiovascular Diseases Cessation of life Chemicals Computer Assisted Data Development Disease Dose Drug Design Drug Kinetics Endothelium Europe Exhibits Extracellular Protein Future Glycoproteins Goals Hemorrhage Hemostatic function Immune response Impairment In Vitro Inflammation Injections Integrins Investigational New Drug Application Knockout Mice Lead Leukocytes Ligand Binding Ligands Macrophage-1 Antigen Mediating Megakaryocytes Molecular Conformation Mus Myocardial Infarction Neutrophil Infiltration Pathologic Pathology Patients Peripheral Pharmaceutical Preparations Platelet Adhesiveness Platelet aggregation Protein Disulfide Isomerase Protein Inhibition Risk Series Signal Pathway Signal Transduction Signaling Molecule Specificity Stroke Surface Tail Techniques Technology Tertiary Protein Structure Testing Therapeutic Thrombosis Thrombus Tissues Toxic effect Vasculitis atherothrombosis conditional knockout drug metabolism efficacy study high throughput screening improved in vivo inhibitor/antagonist mouse model neutrophil nonhuman primate novel novel therapeutics platelet function preclinical study prevent receptor scaffold small molecule small molecule inhibitor targeted treatment therapeutically effective thromboinflammation vascular inflammation

项目摘要

Project Summary Thromboinflammatory diseases, including atherothrombosis, stroke and peripheral vasculitis, result in >30% of all deaths globally. Underlying the pathology of thromboinflammation is increased adhesiveness of platelets and leukocytes. Although many antiplatelet and anti-inflammatory therapies have been used for disease treatment, these drugs increase the risk of major bleeding or impair immune responses. Using protein disulfide isomerase (PDI) conditional knockout (CKO) mice and inhibitors, we and others have shown that extracellular PDI is crucial for platelet thrombus formation in arterial thrombosis and neutrophil recruitment to inflamed endothelium in vascular inflammation. However, inhibition of extracellular PDI with a function-blocking antibody prolongs tail bleeding times in mice, raising a concern that specific inhibition of PDI may perturb hemostatic function. Our recent studies have demonstrated that platelet-released PDI promotes the ligand-binding function of glycoprotein Ibα (GPIbα) and enhances GPIbα-mediated platelet adhesiveness, platelet-neutrophil aggregation and vascular occlusion under thromboinflammatory conditions. These results suggest that inhibitors blocking the PDI-GPIbα signaling axis may be a novel antithromboinflammatory drug. Using high throughput screening, we have identified one compound that specifically inhibits PDI-GPIbα binding and GPIbα-mediated platelet aggregation. We have found that iv injection of the compound into mice abolishes platelet-neutrophil interactions and improves blood flow rates in microvessels under thromboinflammatory conditions. Unlike a conventional inhibitor of PDI or GPIbα, treatment with our compound does not prolong tail bleeding times in mice. These results have provided evidence for the feasibility of identifying small-molecule inhibitors targeting a specific PDI signaling pathway. In Aim 1, using the computer-aided drug design technique and a series of in vitro studies, we will identify small- molecule compounds that specifically block PDI-GPIbα signaling and GPIbα-mediated platelet functions. In Aim 2, we will synthesize derivatives of hits, test them in animal studies and examine DMPK profiles of the selected compounds. The proposed study will prove that compared to conventional inhibition of PDI or GPIbα, specific inhibition of the PDI-GPIbα signaling axis might be a safer and effective therapeutic strategy for treating thromboinflammatory disease.

项目总结