Discovery of small molecules to block fusion and entry of dengue and other env vi
发现小分子以阻止登革热和其他环境病毒的融合和进入
基本信息
- 批准号:8233434
- 负责人:
- 金额:$ 31.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-03-01 至 2014-02-28
- 项目状态:已结题
- 来源:
- 关键词:AffinityAreaBiological AssayCell fusionCellular MembraneChild health careComplexDengueDengue VirusE proteinEventFlavivirusGoalsHumanIndividualInfectionLibrariesMembrane FusionMembrane LipidsMethodsMolecular ConformationNew EnglandOccupationsPeptidesProcessReactionResearchScreening procedureSerotypingStructureTherapeutic InterventionVaccinesViralVirionVirusVirus InhibitorsWest Nile virusWorkbiodefenseconformerenv Gene Productshigh throughput screeninginfluenzavirusinhibitor/antagonistneutralizing antibodypathogenpeptide structurescaffoldsmall moleculestemvironvirus envelope
项目摘要
Enveloped viruses enter and infect cells by fusion of viral and cellular membranes. The fusion step is a
potential target for therapeutic intervention, just as it is the taret of inhibition by some neutralizing
antibodies. We propose four aims, (1) From the structure of the dengue virus envelope protein in its
trimeric, postfusion conformation, we have developed a high throughput screen for small molecule inhibitors
of viral entry. We will further characterize a set of compounds we have recently identified (for dengue virus
type 2) that inhibit viral infectivity in culture, and we will screen new libraries to identify additional compounds
scaffolds. We will examine the extent to which these compounds inhibit other flaviviruses, starting with other
dengue virus serotypes and West Nile virus (WNV). (2) We have found that peptides from the so-called
"stem" segment of the dengue virus E protein inhibit viral infectivity. Inhibition correlates with affinity of the
peptides for the trimeric, low-pH induced conformer of the E protein ectodomain, consistent with the notion
that they inhibit the "zipping up" step in the fusion reaction. We will determine the structures of peptide-
ectodomain complexes and work out the mechanism by which these peptides inhibit entry. (3) We have
developed (initially for influenza virus) a fusion assay that follows the kenetics of individual, single viron
fusion events. We will use this assay to study dengue and WNV mechanisms and to correlate
structure and mechanism for inhibitition of fusion by small molecules and peptides. We will also study the
influence of target-membrane lipid composition on the fusion process. (4) We will develop a higher-
throughput format for the single-virion fusion assay. The ultimate goal is to apply the method for screening
fusion inhibitors and analyzing neutralizing antibodies.
包膜病毒通过病毒和细胞膜的融合进入细胞并感染细胞。聚变步骤是a
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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STEPHEN COPLAN HARRISON其他文献
STEPHEN COPLAN HARRISON的其他文献
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{{ truncateString('STEPHEN COPLAN HARRISON', 18)}}的其他基金
Structural biology of antibody:antigen complexes
抗体的结构生物学:抗原复合物
- 批准号:
8516984 - 财政年份:2013
- 资助金额:
$ 31.92万 - 项目类别:
Structural biology of antibody:antigen complexes
抗体的结构生物学:抗原复合物
- 批准号:
8377204 - 财政年份:2012
- 资助金额:
$ 31.92万 - 项目类别:
Structural biology of antibody:antigen complexes
抗体的结构生物学:抗原复合物
- 批准号:
8329266 - 财政年份:2011
- 资助金额:
$ 31.92万 - 项目类别:
Project 4: Structural Biology of Influenza Antibody-Antigen Interactions
项目4:流感抗体-抗原相互作用的结构生物学
- 批准号:
10549614 - 财政年份:2011
- 资助金额:
$ 31.92万 - 项目类别:
Structure-function analysis of infection- and vaccine-induced B-cell repertoires
感染和疫苗诱导的 B 细胞库的结构功能分析
- 批准号:
10549602 - 财政年份:2011
- 资助金额:
$ 31.92万 - 项目类别:
Structure-function analysis of infection- and vaccine-induced B-cell repertoires
感染和疫苗诱导的 B 细胞库的结构功能分析
- 批准号:
8516979 - 财政年份:2011
- 资助金额:
$ 31.92万 - 项目类别:
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