Novel therapeutics targeting the membrane proximal external region of HIV-1 Env
Novel therapeutics targeting the membrane proximal external region of HIV-1 Env
批准号:
9513722
负责人:
Bing Chen
金额:
$67.38万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-07-19 至 2019-06-30
关键词:
Adverse effectsAntibodiesAntigensAntiviral AgentsBindingBinding SitesBiological AssayCCR5 geneCXCR4 geneCell fusionCell membraneCellsChronicCleaved cellClinicalComplexDrug resistanceEffectivenessEffector CellEpitopesEventExhibitsFDA approvedFc ReceptorGlycoproteinsGoalsHIV Envelope Protein gp120HIV-1ImmuneImmunologyInfectionLeadLibrariesMediatingMembraneMembrane FusionMembrane PotentialsMolecularMolecular ConformationMolecular Mechanisms of ActionMolecular TargetN-terminalPatientsPeptidesPharmaceutical ChemistryPharmaceutical PreparationsPreclinical TestingProtein BiochemistryProvirusesReagentRegimenResearchResolutionSIVSideStructureStructure-Activity RelationshipSurfaceT-20TestingTherapeuticTherapeutic antibodiesVaccinesViralVirionVirus InhibitorsX-Ray Crystallographyantiretroviral therapybasecompliance behaviordesigngp160high throughput screeningimprovedinhibitor/antagonistkillingsneutralizing antibodynew therapeutic targetnovelnovel therapeuticsreceptorscreeningsmall moleculestructural biologytherapeutic candidatetherapeutic targettransmission processvirology
中文摘要
项目摘要
联合抗逆转录病毒疗法(CART)已经将HIV-1感染从曾经的致命疾病转变为
慢性病是可控制的。最新的CART方案使用了几类抗病毒治疗药物和一种
典型的治疗方法需要至少两个类别的三种或三种以上药物的组合。抗药性,
严重的副作用和治疗依从性方面的困难给实施
CART在临床环境中的应用,并表明需要额外的分子靶点。HIV-1病毒的第一个关键步骤
感染是由病毒包膜糖蛋白(Env)介导的病毒与靶细胞膜的融合。恩福韦林
是FDA批准的第一种也是唯一一种融合抑制剂,但其局限性限制了其长期应用
使用。此外,目前的治疗方法不能治愈,因为它们不能消除潜伏的艾滋病毒-1宿主
窝藏着整合的前病毒。基于抗体的疗法,可以有效地抑制HIV-1的进入,还
促进对表达Env的细胞的杀伤是很有希望的消除病毒策略的候选。这个
HIV-1env的膜近端外区(MPER)是一个特别有吸引力的融合抑制物靶点
因为它是整个HIV-1环境中最保守和功能最关键的区域之一。此外,我们
我已经确定了几种MPER定向的HIT化合物,它们可以特异性地抑制膜融合介导的
通过HIV-1环境,但不是SIV环境。此外,MPER特异性的bNAbs在阻断方面表现出非凡的广泛性
它们是开发治疗性抗体的极佳候选者。在这个项目中,我们
假设HIV-1 env的MPER是开发小分子和
基于抗体的病毒膜融合抑制物。我们将带来疫苗方面的最新进展
HIV-1研究寻找新的治疗方法。我们将追求以下具体目标:1)我们将
寻找针对HIV-1 env MPER的小分子融合抑制剂;2)我们将优化小分子
针对MPER的融合抑制剂;3)我们将开发针对MPER的抗体疗法。
当该项目完成后,它不仅将为临床前试验提供线索,而且还将提供新的
进一步剖析HIV-1侵入分子机制的试剂。
英文摘要
Project Summary
Combination antiretroviral therapy (cART) has transformed HIV-1 infection, once a fatal illness, to a
manageable chronic condition. The latest cART regimen uses several classes of antiviral therapeutics and a
typical therapy requires a combination of three or more drugs from at least two classes. Drug resistance,
severe side effects and difficulties in treatment compliance have brought challenges to the implementation of
cART in clinical settings and indicate the need for additional molecular targets. The first critical step of HIV-1
infection is fusion of viral and target cell membranes mediated by viral envelope glycoprotein (Env). Enfuvirtide
is the first and still the only fusion inhibitor approved by FDA, but its limitations have restricted its long-term
use. Moreover, the current therapies are not curative since they cannot eliminate latent HIV-1 reservoirs
harboring integrated proviruses. Antibody-based therapeutics that can potently inhibit HIV-1 entry and also
facilitate killing of Env-expressing cells are promising candidates for reservoir-eliminating strategies. The
membrane proximal external region (MPER) of HIV-1 Env is a particularly attractive target for fusion inhibitors
because it is one of the most conserved and functionally critical regions of the entire HIV-1 Env. Moreover, we
have identified several MPER-directed hit compounds that can specifically inhibit membrane fusion mediated
by HIV-1 Env but not SIV Env. Furthermore, the MPER-specific bnAbs exhibit extraordinary breadth in blocking
HIV-1 infection and they are excellent candidates for developing therapeutic antibodies. In this project, we
hypothesize that the MPER of HIV-1 Env is a promising therapeutic target for developing small-molecule and
antibody-based inhibitors of viral membrane fusion. We will bring recent advances from the vaccine side of
HIV-1 research into the search for novel therapeutics. We will purse the following specific aims: 1) we will
identify small-molecule fusion inhibitors targeting the MPER of HIV-1 Env; 2) we will optimize small-molecule
fusion inhibitors targeting the MPER; 3) we will develop antibody-based therapeutics targeting the MPER.
When the project is completed, it will not only yield leads for preclinical testing, but should also provide novel
reagents for further dissecting molecular mechanisms of HIV-1 entry.
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会议论文
Exploring the membrane-related components of HIV-1 Env for immunogen design
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批准号:10762577
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项目类别:
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资助金额:$84.19万
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财政年份:2023
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负责人:Bing Chen
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依托单位:
Structure of HIV-1 envelope spike in the context of membrane
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批准号:10322988
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项目类别:
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资助金额:$71.03万
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财政年份:2020
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负责人:Bing Chen
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依托单位:
Structure of HIV-1 envelope spike in the context of membrane
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批准号:10538590
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项目类别:
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资助金额:$53.1万
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财政年份:2020
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负责人:Bing Chen
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依托单位:
Structure of the full-length spike protein of SARS-CoV-2 in the context of membrane
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批准号:10117733
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项目类别:
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资助金额:$53.1万
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财政年份:2020
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负责人:Bing Chen
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依托单位:
Structure of HIV-1 envelope spike in the context of membrane
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批准号:10013609
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项目类别:
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资助金额:$53.1万
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财政年份:2020
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负责人:Bing Chen
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依托单位:
Structural Basis of Coreceptor Recognition by HIV-1 Envelope Spike
-
批准号:10390469
-
项目类别:
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资助金额:$52.18万
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财政年份:2018
-
负责人:Bing Chen
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依托单位:
Structural Basis of Coreceptor Recognition by HIV-1 Envelope Spike
-
批准号:9906847
-
项目类别:
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资助金额:$52.6万
-
财政年份:2018
-
负责人:Bing Chen
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依托单位:
Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
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批准号:10653205
-
项目类别:
-
资助金额:$81.62万
-
财政年份:2016
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负责人:Bing Chen
-
依托单位:
Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
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批准号:10449192
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项目类别:
-
资助金额:$81.61万
-
财政年份:2016
-
负责人:Bing Chen
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依托单位:
Small-Molecule Fusion Inhibitors Targeting a Fusion Intermediate State of HIV-1 g
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批准号:8901482
-
项目类别:
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资助金额:$43.96万
-
财政年份:2014
-
负责人:Bing Chen
-
依托单位:
Crystallographic studies of intact and fully glycosylated HIV-1 gp120
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批准号:8603481
-
项目类别:
-
资助金额:$41.26万
-
财政年份:2013
-
负责人:Bing Chen
-
依托单位:
Crystallographic studies of intact and fully glycosylated HIV-1 gp120
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批准号:8663835
-
项目类别:
-
资助金额:$44.15万
-
财政年份:2013
-
负责人:Bing Chen
-
依托单位:
Crystallographic studies of intact and fully glycosylated HIV-1 gp120
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批准号:9053443
-
项目类别:
-
资助金额:$44.25万
-
财政年份:2013
-
负责人:Bing Chen
-
依托单位:
Crystallographic studies of intact and fully glycosylated HIV-1 gp120
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批准号:8836951
-
项目类别:
-
资助金额:$44.25万
-
财政年份:2013
-
负责人:Bing Chen
-
依托单位:
HIV-1 GP41 ARE RECOGNIZED BY NEUTRALIZING AND NON-NEUTRALIZING ANTIBODIES
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批准号:8361720
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项目类别:
-
资助金额:$0.26万
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财政年份:2011
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负责人:Bing Chen
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依托单位:
HIV-1 PRIMARY RECEPTOR CD4 IN COMPLEX WITH A POTENT ANTIVIRAL ANTIBODY
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批准号:8361719
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项目类别:
-
资助金额:$0.25万
-
财政年份:2011
-
负责人:Bing Chen
-
依托单位:
Biochemical and structural studies of distinct conformational states of gp41
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批准号:8055554
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项目类别:
-
资助金额:$35.18万
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财政年份:2009
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负责人:Bing Chen
-
依托单位:
Biochemical and structural studies of distinct conformational states of gp41
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批准号:8243563
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项目类别:
-
资助金额:$35.39万
-
财政年份:2009
-
负责人:Bing Chen
-
依托单位:
Biochemical and structural studies of distinct conformational states of gp41
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批准号:7790795
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项目类别:
-
资助金额:$35.23万
-
财政年份:2009
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负责人:Bing Chen
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依托单位:
Biochemical and structural studies of distinct conformational states of gp41
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批准号:8440765
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项目类别:
-
资助金额:$34.15万
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财政年份:2009
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负责人:Bing Chen
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依托单位:
海外基金