Probing functional HIV-1 envelope glycoprotein conformations with novel potent CD4-mimetic compounds
用新型有效的 CD4 模拟化合物探测功能性 HIV-1 包膜糖蛋白构象
基本信息
- 批准号:10762703
- 负责人:
- 金额:$ 88.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-10 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:Animal ModelAntibodiesBindingBinding SitesCCR5 geneCD4 AntigensCXCR4 geneCell membraneCellsConsentElementsExhibitsGlycoproteinsHIVHIV Envelope Protein gp120KnowledgeLeadMediatingMembraneMembrane FusionMolecular ConformationMonkeysMucous MembranePhenylalaninePredispositionProteinsReceptor CellResistanceSamplingStructureSurfaceTestingTherapeuticVaccinesVaginaVariantVestibuleViralVirionVirusVirus DiseasesVirus ReplicationWritinganaloganti-viral efficacyantibody-dependent cell cytotoxicitycostcytotoxicdesignfitnesshumanized mouseimprovedindolineinhibitormimeticsneutralizing antibodynovelprematureprophylacticprototyperational designreceptorscaffoldsimian human immunodeficiency virussmall moleculesynergismviral resistancevirus envelope
项目摘要
PROJECT SUMMARY/ABSTRACT
The human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer ((gp120-gp41)3) binds to host
receptors, CD4 and CCR5/CXCR4, and mediates the entry of the virus into the target cell. CD4 binding induces
large-scale conformational changes in the metastable Env trimer, resulting in transitions from a pretriggered,
“closed” conformation to more “open” conformations. The CD4-induced opening of the Env trimer allows the
gp120 subunit to bind the CCR5/CXCR4 coreceptor, which enables the fusion of viral and target cell membranes
by the gp41 transmembrane subunit.
CD4-mimetic compounds (CD4mcs) are small organic molecules that bind to a highly conserved pocket (the
Phe-43 cavity) on gp120, near the binding site for CD4. CD4mcs competitively block CD4 binding and
prematurely trigger conformational changes in Env similar to those induced by CD4. In the absence of a
coreceptor-expressing target cell, these prematurely activated Envs rapidly and irreversibly become non-
functional. At sub-inhibitory concentrations, CD4mcs open Env to the binding of antibodies that consequently
acquire neutralizing or cytotoxic potential. CD4mcs can synergize with antibodies to decrease the HIV-1-infected
cell reservoir in humanized mice and to protect monkeys from a heterologous SHIV mucosal challenge.
The CD4mc scaffold, which occupies the gp120 “vestibule” leading into the Phe-43 cavity, is a critical determinant
of the antiviral potential of these compounds. Replacing the tetramethyl-piperidine scaffold of the prototypic
CD4mcs with an indane scaffold opened the door to rationally designed improvements in antiviral potency and
breadth. Nonetheless, some primary HIV-1 strains with apparently accessible Phe-43 cavities remain relatively
resistant to current lead indane CD4mcs. We have recently identified novel CD4mc analogues with indoline
scaffolds that demonstrate impressive increases in antiviral potency and breadth. In this proposal, we capitalize
on this discovery to design further improvements in the indoline CD4mcs, to investigate the mechanisms
underlying their antiviral potency, and to determine how natural HIV-1 Env variation influences virus resistance
to CD4mcs and viral replication fitness. In the course of these studies, we will test the following hypotheses:
Hypothesis 1: Increasing the contacts of the indoline CD4mcs with conserved gp120 elements in the vestibule
will further enhance their antiviral potency and breadth; Hypothesis 2: Although CD4mc resistance in a small
subset of HIV-1 strains results from variation within the Phe-43 cavity, the sensitivity of most primary HIV-1
strains to CD4mcs is governed by differences in Env triggerability (the propensity of the Env to undergo
conformational change); and Hypothesis 3: CD4mcs gain potency by enhanced binding to the Env trimer,
leading to sequential activation and inactivation that ultimately result in gp120 shedding.
The knowledge generated by testing these hypotheses will assist efforts to improve the antiviral efficacy of
CD4mcs and will enhance their utility as small-molecule probes of HIV-1 Env conformation.
项目总结/文摘
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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WAYNE A. HENDRICKSON其他文献
WAYNE A. HENDRICKSON的其他文献
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{{ truncateString('WAYNE A. HENDRICKSON', 18)}}的其他基金
Structural studies of HCN channels in health and disease
HCN通道在健康和疾病中的结构研究
- 批准号:
10197240 - 财政年份:2019
- 资助金额:
$ 88.9万 - 项目类别:
Structural Studies of HCN Channels in Health and Disease
健康和疾病中 HCN 通道的结构研究
- 批准号:
10647829 - 财政年份:2019
- 资助金额:
$ 88.9万 - 项目类别:
Structural studies of HCN channels in health and disease
HCN通道在健康和疾病中的结构研究
- 批准号:
10438777 - 财政年份:2019
- 资助金额:
$ 88.9万 - 项目类别:
Center on Membrane Protein Production and Analysis (COMPPAA)
膜蛋白生产和分析中心 (COMPPAA)
- 批准号:
9268638 - 财政年份:2016
- 资助金额:
$ 88.9万 - 项目类别:
Generic Assays for Functional Characterization (548-591)
功能表征的通用分析 (548-591)
- 批准号:
9050048 - 财政年份:2016
- 资助金额:
$ 88.9万 - 项目类别:
Efficient Production of Recombinant Membrane Proteins (459-501)
重组膜蛋白的高效生产 (459-501)
- 批准号:
9050045 - 财政年份:2016
- 资助金额:
$ 88.9万 - 项目类别:
Anomalous Diffraction Analysis of Biomolecular Structure
生物分子结构的反常衍射分析
- 批准号:
8858645 - 财政年份:2014
- 资助金额:
$ 88.9万 - 项目类别:
Anomalous Diffraction Analysis of Biomolecular Structure
生物分子结构的反常衍射分析
- 批准号:
8697562 - 财政年份:2014
- 资助金额:
$ 88.9万 - 项目类别:
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