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Evaluation of in vitro and in vivo efficacy of glycan-based compounds against flavivirus endothelial permeability and vascular leak

聚糖基化合物对抗黄病毒内皮通透性和血管渗漏的体外和体内功效评估

基本信息

批准号：
10115592
负责人：
Eva Harris
金额：
$ 20万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
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：
2020-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115592
关键词：
Address Agaricus Americas Anticoagulants Antiviral Agents Arbovirus Infections Binding Biological Biological Assay Biological Availability Blood Vessels Case Management Cathepsin L Cells Characteristics Collaborations Complex Confocal Microscopy Congenital Abnormality Cyclodextrins Dengue Dengue Infection Dengue Virus Disease Electrical Resistance Endothelial Cells Endothelium Epidemic Evaluation Extravasation Flavivirus Functional disorder Glycocalyx Glycosaminoglycans Guillain Barré Syndrome Heparitin Sulfate Human Immune Immune Evasion In Vitro Infection Inflammatory Location Measures Mediating Medical Methods Modality Molecular Conformation Molecular Weight Morbidity - disease rate Mus Nonstructural Protein Pathogenesis Pathway interactions Peripheral Blood Mononuclear Cell Permeability Pharmaceutical Preparations Play Polysaccharides Prevention Production Proteins Public Health RNA replication Role Route Safety Series Sialic Acids Structure Structure-Activity Relationship Sulfate Targeted Research Testing Therapeutic Therapeutic Agents Toxic effect Viral Load result Viral Nonstructural Proteins Viral Pathogenesis Viral Proteins Virus Virus Diseases ZIKA ZIKV disease ZIKV infection Zika Virus analog base beta-Cyclodextrins beta-Glucans cytokine cytotoxicity design endothelial dysfunction fungus glucuronyl glucosamine glycan sulfate heparanase human disease improved in vitro activity in vivo inhibitor/antagonist innovation mimetics mortality mosquito-borne mouse model novel novel therapeutic intervention preservation prevent protective effect sugar syndecan viral RNA

项目摘要

ABSTRACT Dengue (DENV) and Zika (ZIKV) viruses are mosquito-borne viruses that are major medical and public health problems worldwide. DENV causes the most prevalent mosquito-borne viral disease of humans, and severe cases manifesting vascular leakage can be fatal. The related Zika virus (ZIKV) recently caused explosive epidemics across the Americas and has been associated with congenital birth defects and Guillain-Barré syndrome. Despite their substantial worldwide morbidity and mortality, no therapeutic agents exist for treatment of dengue or Zika. Nonstructural protein 1 (NS1) is a flaviviral protein that participates in viral RNA replication and in its secreted form plays important roles in host immune evasion and viral pathogenesis. We and others recently described novel roles for NS1 in directly triggering endothelial barrier dysfunction and inducing inflammatory cytokine production from human immune cells, contributing to vascular leak in vivo. In this proposal, we will evaluate the in vitro and in vivo efficacy of glycans against NS1-mediated pathogenesis, as well as against DENV and ZIKV infection in vivo. We have developed multiple methods to study DENV and ZIKV pathogenesis based on characterization of NS1-induced endothelial barrier dysfunction in vitro (e.g., hyper- permeability, disruption of the endothelial glycocalyx-like layer [EGL]) and in vivo, using murine models of virus- and NS1-induced disease with vascular leakage. Our preliminary results showing that a sulfated derivative of β- glucan from Agaricus brasiliensis fungus (FR-S) has a protective effect in vitro and in vivo against DENV NS1- induced endothelial hyperpermeability are promising. We have also shown that FR-S has anti-DENV and anti- ZIKV activity in vitro. In collaboration with Dr. K. Godula (UC San Diego) we determined that specific synthetic GAG-mimetic molecules efficiently bind to flavivirus NS1. Given the contribution of NS1 to flavivirus pathogenesis and our preliminary results, we hypothesize that glycans inhibit NS1-induced EGL degradation and vas- cular leakage in vivo as well as viral infection and have potential as novel treatment modalities for dengue and Zika. The approach is innovative in that we target inhibition of severe disease manifestations, in addition to antiviral activity. Aim 1 will select the most promising inhibitor(s) of NS1-induced pathophysiological pathways of DENV and ZIKV based on prevention of endothelial dysfunction in vitro. We will screen 27 glycans, including FR and FR-S, 4 GAG-mimetics, sulodexide, and 20 cyclodextrin analogues (in collaboration with Dr. T. Sohajda, CycloLab), for their ability to prevent NS1-induced hyperpermeability. Aim 2 will investigate the in vitro mechanism of action of prevention of endothelial dysfunction by the selected compounds. Aim 3 will evaluate the therapeutic potential of the most active compounds against DENV and ZIKV NS1- and virus-induced vascular leak, morbidity, and mortality in vivo. Overall, this proposal address- es a critical need, identifying novel therapeutic strategies against two major flaviviral diseases, by developing glycan-based compounds that target both the virus and pathophysiological consequences of infection.

摘要