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
项目总结
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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专著(0)
科研奖励(0)
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
-
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:
-
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
-
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:
-
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
-
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:
-
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
-
依托单位:
Structural Basis of Coreceptor Recognition by HIV-1 Envelope Spike
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批准号:9906847
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项目类别:
-
资助金额:$52.6万
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财政年份:2018
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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
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批准号:10390469
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项目类别:
-
资助金额:$52.18万
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财政年份:2018
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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:10653205
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项目类别:
-
资助金额:$81.62万
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财政年份:2016
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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:10449192
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项目类别:
-
资助金额:$81.61万
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财政年份:2016
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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
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项目类别:
-
资助金额:$43.96万
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财政年份:2014
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负责人:Bing Chen
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依托单位:
Crystallographic studies of intact and fully glycosylated HIV-1 gp120
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批准号:8603481
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项目类别:
-
资助金额:$41.26万
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财政年份:2013
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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
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项目类别:
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资助金额:$44.15万
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财政年份:2013
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负责人:Bing Chen
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依托单位:
Crystallographic studies of intact and fully glycosylated HIV-1 gp120
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批准号:9053443
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项目类别:
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资助金额:$44.25万
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财政年份:2013
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负责人:Bing Chen
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依托单位:
Crystallographic studies of intact and fully glycosylated HIV-1 gp120
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批准号:8836951
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项目类别:
-
资助金额:$44.25万
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财政年份:2013
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负责人:Bing Chen
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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:
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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
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财政年份:2011
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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: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
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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:8243563
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项目类别:
-
资助金额:$35.39万
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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:
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
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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:
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