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:
- 金额:$ 20万
- 依托单位:
- 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:
- 关键词:AddressAgaricusAmericasAnticoagulantsAntiviral AgentsArbovirus InfectionsBindingBiologicalBiological AssayBiological AvailabilityBlood VesselsCase ManagementCathepsin LCellsCharacteristicsCollaborationsComplexConfocal MicroscopyCongenital AbnormalityCyclodextrinsDengueDengue InfectionDengue VirusDiseaseElectrical ResistanceEndothelial CellsEndotheliumEpidemicEvaluationExtravasationFlavivirusFunctional disorderGlycocalyxGlycosaminoglycansGuillain Barré SyndromeHeparitin SulfateHumanImmuneImmune EvasionIn VitroInfectionInflammatoryLocationMeasuresMediatingMedicalMethodsModalityMolecular ConformationMolecular WeightMorbidity - disease rateMusNonstructural ProteinPathogenesisPathway interactionsPeripheral Blood Mononuclear CellPermeabilityPharmaceutical PreparationsPlayPolysaccharidesPreventionProductionProteinsPublic HealthRNA replicationRoleRouteSafetySeriesSialic AcidsStructureStructure-Activity RelationshipSulfateTargeted ResearchTestingTherapeuticTherapeutic AgentsToxic effectViral Load resultViral Nonstructural ProteinsViral PathogenesisViral ProteinsVirusVirus DiseasesZIKAZIKV diseaseZIKV infectionZika Virusanalogbasebeta-Cyclodextrinsbeta-Glucanscytokinecytotoxicitydesignendothelial dysfunctionfungusglucuronyl glucosamine glycan sulfateheparanasehuman diseaseimprovedin vitro activityin vivoinhibitor/antagonistinnovationmimeticsmortalitymosquito-bornemouse modelnovelnovel therapeutic interventionpreservationpreventprotective effectsugarsyndecanviral 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Eva Harris其他文献
Eva Harris的其他文献
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{{ truncateString('Eva Harris', 18)}}的其他基金
The evolution of dengue virus-reactive circulating antibody repertoire
登革热病毒反应性循环抗体库的进化
- 批准号:
10647572 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Host factors and viral determinants mediating flavivirus NS1 tissue-specific endothelial dysfunction and vascular leak
介导黄病毒 NS1 组织特异性内皮功能障碍和血管渗漏的宿主因素和病毒决定因素
- 批准号:
10610896 - 财政年份:2022
- 资助金额:
$ 20万 - 项目类别:
Host factors and viral determinants mediating flavivirus NS1 tissue-specific endothelial dysfunction and vascular leak
介导黄病毒 NS1 组织特异性内皮功能障碍和血管渗漏的宿主因素和病毒决定因素
- 批准号:
10417735 - 财政年份:2022
- 资助金额:
$ 20万 - 项目类别:
Living in the post-Zika world: Impact of interactions between dengue and Zika viruses on diagnostics, antibody dynamics, and correlates of disease risk
生活在后寨卡世界:登革热和寨卡病毒之间的相互作用对诊断、抗体动态和疾病风险相关性的影响
- 批准号:
10615774 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Living in the post-Zika world: Impact of interactions between dengue and Zika viruses on diagnostics, antibody dynamics, and correlates of disease risk
生活在后寨卡世界:登革热和寨卡病毒之间的相互作用对诊断、抗体动态和疾病风险相关性的影响
- 批准号:
10450165 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Living in the post-Zika world: Impact of interactions between dengue and Zika viruses on diagnostics, antibody dynamics, and correlates of disease risk
生活在后寨卡世界:登革热和寨卡病毒之间的相互作用对诊断、抗体动态和疾病风险相关性的影响
- 批准号:
10297285 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Project 1 - Immune profiling of natural dengue virus infections
项目 1 - 天然登革热病毒感染的免疫分析
- 批准号:
10428796 - 财政年份:2020
- 资助金额:
$ 20万 - 项目类别:
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
- 批准号:
9979169 - 财政年份:2020
- 资助金额:
$ 20万 - 项目类别:
Administrative Supplement to R21: Mechanism and in vivo activity of novel glycan-based therapy against flavivirus endothelial permeability and vascular leak
R21 的行政补充:针对黄病毒内皮通透性和血管渗漏的新型聚糖疗法的机制和体内活性
- 批准号:
10265787 - 财政年份:2020
- 资助金额:
$ 20万 - 项目类别:
Dissecting novel mechanisms of dengue virus NS1-induced vascular leak
剖析登革热病毒 NS1 诱导血管渗漏的新机制
- 批准号:
9221261 - 财政年份:2016
- 资助金额:
$ 20万 - 项目类别:
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西南喀斯特地区蘑菇属(Agaricus)真菌网状进化及优良菌株的发掘
- 批准号:31560012
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