A Recombinant Cedar Virus-based Henipavirus Replication Platform for High-throughput Inhibitor Screening
基于重组雪松病毒的亨尼帕病毒复制平台,用于高通量抑制剂筛选
基本信息
- 批准号:9509144
- 负责人:
- 金额:$ 23.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-12-20 至 2019-11-30
- 项目状态:已结题
- 来源:
- 关键词:AnimalsAntiviral AgentsAustraliaBindingBiological AssayCell CommunicationCell Culture TechniquesCell LineCell fusionCell membraneCellsCellular biologyChicagoCollaborationsCommunicable DiseasesContainmentEph Family ReceptorsEphrin-A1Ephrin-B1Far EastGlycoproteinsGrowthHendra VirusHenipavirusHenipavirus InfectionsHumanIllinoisInfectionKineticsLeadLibrariesLivestockLuc GeneLuciferasesLung diseasesMammalsMeasuresMediatingMedicalMembraneMembrane FusionNipah VirusParamyxovirusPathogenicityPublic HealthRNA VirusesReceptor CellRecombinantsReporterReporter GenesResearchSeriesSignal TransductionSurface Plasmon ResonanceSystemTestingTexasTherapeuticTimeTropismUniversitiesVaccinesViralVirionVirusVirus DiseasesVirus ReplicationWorkZoonosesbasebiothreatdrug discoveryexperimental studygenetic approachglycoprotein Ghigh throughput screeninginhibitor/antagonistinsightnervous system disorderneutralizing antibodypathogenrecombinant virusreverse geneticsscreeningsmall moleculesmall molecule librariesvirology
项目摘要
Project Summary/Abstract
The emergence of pathogenic viruses represents continuous infectious disease threats to public health.
Among these, the paramyxoviruses, which include many important human and animal pathogens, also include
two excellent examples of emerged, zoonotic pathogens of importance: the henipaviruses; Hendra virus (HeV)
and Nipah virus (NiV). HeV and NiV have a uniquely broad host tropism capable of infecting at least 18 animal
species across 6 orders of mammals. HeV and NiV can also cause a systemic and often fatal respiratory
and/or neurological disease in 11 mammalian species including humans. These henipaviruses remain
significant biothreats to humans and economically important livestock in Australia and throughout South East
Asia, and there are no vaccines or antivirals approved for human use. The henipaviruses are single-stranded,
negative sense, enveloped RNA viruses and possess two membrane anchored glycoproteins involved in virus
entry, one for host cell receptor attachment (G glycoprotein) and the other a fusion (F) glycoprotein which
facilitates virion and host cell membrane fusion. The G and F glycoproteins are the major antigenic targets of
neutralizing antibodies and also the focus of several vaccine strategies. In contrast however, antiviral drug
discovery for HeV and NiV has been significantly hampered because of the requirements of biosafety level-4
(BSL-4) containment, and presently there is a complete lack of any effective antiviral therapeutics against
henipaviruses for human use. We have been extensively characterizing the recently identified non-pathogenic
species of henipavirus, Cedar virus (CedPV). Using recombinant viral glycoprotein mediated cell-cell fusion
assays, we have discovered that CedPV-mediated membrane fusion is similar to HeV and NiV, however, the
ephrin receptor tropism of CedPV was found to be remarkably broad and fusion could be triggered by ephrin-
B1 and -B2 as well as the glycophosphatidylinositol-anchored A subtype ephrins-A1, -A2, and -A5. The cell-
cell fusion activity supported by each of these ephrin receptors also correlated with CedPV G binding ability as
measured by surface plasmon resonance. Further, we have recently rescued recombinant CedPV encoding
eGFP (rCedPV-GFP) using a reverse genetics approach. Our rCedPV platform represents a new virological
system that can be used in a variety of applications to study various aspects of henipavirus cell biology and
host cell interactions safely under BSL-2 containment. But of further importance, it is also an authentic
henipavirus infection and replication reporter system now suitable for high-throughput screening (HTS) for the
discovery of potentially pan-anti-henipavirus molecules. Using this new live-henipavirus platform, our
objectives here will be to develop and optimize a rCedPV reporter system and utilize it in an HTS assay to
discover antiviral molecules capable of inhibiting the infection of henipaviruses. Specifically, we will: 1) Adapt
and develop CedPV reporters for the HTS assay; 2) Optimize the HTS parameters of recombinant virus
infection and reporter activities; and 3) Pilot a HTS assay using the Prestwick Chemical Library.
项目总结/文摘
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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CHRISTOPHER C BRODER其他文献
CHRISTOPHER C BRODER的其他文献
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{{ truncateString('CHRISTOPHER C BRODER', 18)}}的其他基金
Advancement of Vaccines and Therapies for Henipaviruses
亨尼帕病毒疫苗和治疗的进展
- 批准号:
10581491 - 财政年份:2019
- 资助金额:
$ 23.06万 - 项目类别:
Advancement of Vaccines and Therapies for Henipaviruses
亨尼帕病毒疫苗和治疗的进展
- 批准号:
10362726 - 财政年份:2019
- 资助金额:
$ 23.06万 - 项目类别:
Advancement of Vaccines and Therapies for Henipaviruses
亨尼帕病毒疫苗和治疗的进展
- 批准号:
9897467 - 财政年份:2019
- 资助金额:
$ 23.06万 - 项目类别:
Australian bat lyssavirus tropism entry and host factor dependence
澳大利亚蝙蝠狂犬病病毒的趋向性进入和宿主因子依赖性
- 批准号:
8233373 - 财政年份:2011
- 资助金额:
$ 23.06万 - 项目类别:
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