Mode of Action of Allosteric HIV-1 Integrase Inhibitors during Late Steps of Viral Replication
变构 HIV-1 整合酶抑制剂在病毒复制后期的作用模式
基本信息
- 批准号:9204097
- 负责人:
- 金额:$ 18.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-04 至 2018-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAmino AcidsAnti-Retroviral AgentsAntiviral AgentsAtomic Force MicroscopyBindingBinding SitesBiochemicalBiologyCapsidCellsChromosomesClinicalComplexDefectDevelopmentElectronsElementsEnzymesFoundationsFutureGenomeHIVHIV-1HIV-1 integraseIn VitroInfectionIntegraseIntegrase InhibitorsLinkMapsMass Spectrum AnalysisMembraneMorphogenesisMorphologyNucleosome Core ParticlePatientsPhenotypePhysical condensationPlayProtein FootprintingPublishingRNA BindingRecombinantsReportingResistanceRibonucleoproteinsRoleStagingStructureTimeViralVirionVirusVirus Replicationabstractingbasecofactorimprovedinhibitor/antagonistmutantnovelparticlepyridinequinolineresearch studysuccesstherapeutic targettranscriptional coactivator p75viral DNAviral RNAvirology
项目摘要
Abstract
HIV-1 integrase (IN) is essential for viral replication and catalyzes integration of viral DNA into the
host chromosome. A new class of allosteric IN inhibitors (ALLINIs) has recently been reported to be
capable of inhibiting the enzyme function by promoting aberrant IN multimerization. Unexpectedly, in
infected cells, these compounds potently impaired the late stage of HIV-1 replication by triggering
significant viral core morphology defects. This phenotype suggested that in addition to its known
catalytic function during the early steps of HIV-1 replication, IN also plays an important, non-catalytic
role during the late steps of viral replication. Our preliminary studies reveal that IN tightly binds to
select highly structured viral RNA elements both in vitro and in properly matured virions. In addition,
we were able to observe that an ALLINI is capable of modulating this interaction in the virion. The
following two aims will extend these preliminary observations. Aim 1 will map the viral RNA binding
sites on IN and determine the functional significance of the identified interacting amino acids. Aim 2 will
determine how ALLINIs affect IN interactions with viral RNA during virion morphogenesis. Taken
together, we will use a combination of virology and biochemical approaches to allow us to examine the
potential link between IN interactions with viral RNA genome and formation of properly matured virions.
Structural details that will emerge from these studies will increase our understanding of how IN
functions during the late stage of HIV-1 replication as well as elucidate the mode of action for the
recently discovered ALLINIs.
摘要
HIV-1整合酶(IN)是病毒复制所必需的,并催化病毒DNA整合到
宿主染色体。一类新的变构蛋白抑制剂(ALLINI)最近被报道是
能够通过促进多聚体中的异常来抑制酶的功能。出乎意料的是,在
被感染的细胞,这些化合物通过触发
明显的病毒核心形态缺陷。这一表型表明,除了已知的
在HIV-1复制的早期阶段,IN也起着重要的、非催化的作用
在病毒复制的后期阶段发挥作用。我们的初步研究表明,IN与
在体外和适当成熟的病毒粒子中选择高度结构的病毒RNA元件。此外,
我们能够观察到Allini能够调节病毒粒子中的这种相互作用。这个
以下两个目标将扩展这些初步观察。AIM 1将绘制病毒RNA结合图
并确定识别出的相互作用氨基酸的功能意义。目标2将
确定在病毒粒子形态形成过程中,ALLINI如何影响IN与病毒RNA的相互作用。已被占用
我们将一起使用病毒学和生化方法的组合,使我们能够检查
IN与病毒RNA基因组的相互作用和成熟的病毒粒子的形成之间的潜在联系。
从这些研究中发现的结构细节将增加我们对IN的理解
在HIV-1复制的后期阶段的作用以及阐明
最近发现的等位基因。
项目成果
期刊论文数量(0)
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Jacques J. Kessl其他文献
Jacques J. Kessl的其他文献
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{{ truncateString('Jacques J. Kessl', 18)}}的其他基金
New Inhibitors Targeting HIV-1 Integrase During Viral Maturation
在病毒成熟过程中针对 HIV-1 整合酶的新型抑制剂
- 批准号:
10218004 - 财政年份:2019
- 资助金额:
$ 18.44万 - 项目类别:
New Inhibitors Targeting HIV-1 Integrase During Viral Maturation
在病毒成熟过程中针对 HIV-1 整合酶的新型抑制剂
- 批准号:
10452601 - 财政年份:2019
- 资助金额:
$ 18.44万 - 项目类别:
Role of HIV-1 Integrase in the Late Stage of Viral Replication
HIV-1整合酶在病毒复制后期的作用
- 批准号:
8793750 - 财政年份:2014
- 资助金额:
$ 18.44万 - 项目类别:
Role of HIV-1 Integrase in the Late Stage of Viral Replication
HIV-1整合酶在病毒复制后期的作用
- 批准号:
8732362 - 财政年份:2014
- 资助金额:
$ 18.44万 - 项目类别:
Inhibitors Targeting HIV Integrase Multimers
针对 HIV 整合酶多聚体的抑制剂
- 批准号:
8294551 - 财政年份:2011
- 资助金额:
$ 18.44万 - 项目类别:
Inhibitors Targeting HIV Integrase Multimers
针对 HIV 整合酶多聚体的抑制剂
- 批准号:
8210639 - 财政年份:2011
- 资助金额:
$ 18.44万 - 项目类别:
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