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
登革热(DENV)和寨卡(ZIKV)病毒是蚊子传播的病毒,是主要的医疗和公共卫生问题。
全世界的问题。DENV引起人类最普遍的蚊媒病毒性疾病,
出现血管渗漏的病例可能是致命的。相关寨卡病毒(ZIKV)最近引发爆炸性事件
流行病在整个美洲,并已与先天性出生缺陷和格林-巴利
综合征尽管它们在世界范围内的发病率和死亡率很高,但对于它们没有治疗剂。
治疗登革热或寨卡病毒。非结构蛋白1(NS 1)是一种黄病毒蛋白,参与病毒RNA
病毒复制及其分泌形式在宿主免疫逃避和病毒致病中起重要作用。我们
和其他人最近描述了NS 1在直接触发内皮屏障功能障碍中的新作用,
诱导人免疫细胞产生炎性细胞因子,导致体内血管渗漏。在这
我们将评估聚糖对NS 1介导的发病机制的体外和体内功效,
以及体内抗DENV和ZIKV感染。我们已经开发了多种方法来研究DENV和ZIKV
基于体外NS 1诱导的内皮屏障功能障碍的表征的发病机制(例如,超
渗透性,破坏内皮糖萼样层[EGL])和体内,使用病毒-
和NS 1诱导的疾病伴血管渗漏。我们的初步结果表明β-的硫酸化衍生物
来自巴西蘑菇真菌的葡聚糖(FR-S)在体外和体内对DENV NS 1具有保护作用,
诱导的内皮细胞高通透性是有希望的。我们还表明,FR-S具有抗DENV和抗
体外ZIKV活性。与K博士合作。Godula(UC San Diego),我们确定特定的合成
GAG模拟分子有效地结合黄病毒NS 1。考虑到NS 1对黄病毒发病机制的贡献,
和我们的初步结果,我们假设聚糖抑制NS 1诱导的EGL降解和vas,
以及病毒感染,并有可能作为新的治疗方式,
登革热和寨卡病毒这种方法是创新的,因为我们的目标是抑制严重的疾病表现,
除了抗病毒活性。目的1将选择最有前途的NS 1诱导的抑制剂,
本发明的目的是基于体外预防内皮功能障碍来研究DENV和ZIKV的病理生理学途径。
我们将筛选27种聚糖,包括FR和FR-S,4种GAG模拟物,舒洛地特和20种环糊精类似物
(in与T博士合作Sohajda,CycloLab),因为它们能够防止NS 1诱导的高渗透性。目的
2将研究通过所选的药物预防内皮功能障碍的体外作用机制。
化合物.目的3将评估针对DENV的最具活性的化合物的治疗潜力,
ZIKV NS 1和病毒诱导的体内血管渗漏、发病率和死亡率总的来说,这项建议涉及-
是一个迫切的需要,确定新的治疗策略,对两个主要的黄病毒疾病,通过开发
基于聚糖的化合物,其靶向病毒和感染的病理生理后果。
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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