Development of HIV capsid-targeting antivirals that affect immune response by modulating capsid stability and have improved resistance profiles
开发 HIV 衣壳靶向抗病毒药物,通过调节衣壳稳定性影响免疫反应并改善耐药性
基本信息
- 批准号:10437037
- 负责人:
- 金额:$ 53.81万
- 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:2016-03-16 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAntiviral AgentsAntiviral resistanceBasic ScienceBindingBiological AssayBiophysicsCalorimetryCapsidCapsid ProteinsCellsClinical TrialsCollaborationsComplexCrystallizationCrystallographyDataDevelopmentDisclosureDrug KineticsDrug TargetingDrug resistanceElectron MicroscopyFundingGenesHIVHIV-1ImageImmuneImmune EvasionImmune responseImmunologic SurveillanceIn VitroInfectionInjectableIntegration Host FactorsInterferonsKineticsLeadLengthLettersLife Cycle StagesManuscriptsMediatingMetabolicMinnesotaMolecularMonitorMutationNuclearPatientsPeptidesPharmaceutical PreparationsPharmacologyPhase II/III Clinical TrialPlayPropertyProteinsProtomerPublishingReportingResearchResistanceResistance profileReverse TranscriptionRoleSamplingSeriesSiteSolubilityStructureStructure-Activity RelationshipTREX1 geneTherapeuticTimeUp-RegulationViralVirusX-Ray Crystallographyanalogantagonistbasebiophysical analysischemical synthesiscrosslinkcytotoxicitydesignearly phase clinical trialimprovedin vivoinhibitorinnovationintegration siteinventionknockout genemutantnovelnovel strategiesprematureresistance mutationresponsesynergismtooltranslational studyviral DNAvirology
项目摘要
PROJECT SUMMARY
The HIV-1 capsid (CA) is a protein that plays a major role in multiple steps of the virus life cycle. During the
previous funding cycle we solved the elusive structure of the intact native full length hexameric HIV-1 CA
revealing previously unknown molecular details, especially at the 3-fold and 2-fold intra-hexamer interfaces that
affect core stability. We also solved >45 CA structures that include mutations that modulate core stability, thus
providing the first glimpses of the molecular basis of core stabilization that is critical in designing potential
therapeutics. Additional structures were in complex with host factor peptides, or a variety of novel inhibitors. In
addition, we synthesized and characterized >220 compounds that target the PF74-binding pocket. Among them
are compounds with much higher potency than PF74, and importantly, compounds with improved resistance
profile compared to GS-6207, a highly potent CA-targeting drug in clinical trials. In addition to strong CA hexamer
stabilizers, we introduced an innovative class of compounds, “destabilizers” of CA hexamers, raising the exciting
prospect of core destabilization that may lead to premature capsid uncoating and interferon upregulation.
We will use a combination of chemical synthesis, virological, biophysical, and crystallography approaches to
synthesize a number of compounds that improve potency through new inter- and intra-protomer interactions;
overcome GS-6207 resistance mutations; modulate core stability and upregulate interferon response; enable
interactions with CA through innovative mechanisms, including covalent crosslinking. The compounds will be
characterized and the structure activity relationship studies will be guided by X-ray crystallography, biophysical
studies (time-lapse imaging, thermal shift, assembly kinetics assays) and virological characterization of
mechanism of action as well as drug resistance studies. The research will be conducted by the groups of Stefan
Sarafianos at Emory Univ (structure, biophysics, virology) and ZQ Wang (chemical synthesis, Univ of
Minnesota), Eric Freed at DRP-NCI (virology), and in collaboration with Greg Melikian (imaging).
The proposed studies will advance our understanding of the structural basis of core stability, which controls a
large number of steps in the virus life cycle. They will also lead to the identification of innovative compound leads
with novel “CA-destabilizing” mechanisms of action, high potency, improved resistance profiles, CA-crosslinking
functionalities, and improved pharmacological properties.
项目概要
HIV-1 衣壳 (CA) 是一种在病毒生命周期的多个步骤中发挥重要作用的蛋白质。期间
在之前的资助周期中,我们解决了完整的天然全长六聚体 HIV-1 CA 的难以捉摸的结构
揭示了以前未知的分子细节,特别是在 3 倍和 2 倍六聚体内界面处
影响核心稳定性。我们还解决了超过 45 个 CA 结构,其中包括调节核心稳定性的突变,因此
首次了解核心稳定的分子基础,这对于设计潜力至关重要
疗法。其他结构与宿主因子肽或各种新型抑制剂形成复合物。在
此外,我们还合成并表征了超过 220 种针对 PF74 结合袋的化合物。他们之中
是比 PF74 效力高得多的化合物,而且重要的是,这些化合物具有更高的耐受性
与临床试验中的高效 CA 靶向药物 GS-6207 相比。除了强CA六聚体
稳定剂,我们推出了一类创新化合物,CA 六聚体“去稳定剂”,提高了令人兴奋的
核心不稳定的前景可能导致衣壳过早脱壳和干扰素上调。
我们将结合化学合成、病毒学、生物物理和晶体学方法来
合成了许多通过新的原体间和原体内相互作用提高效力的化合物;
克服GS-6207耐药突变;调节核心稳定性并上调干扰素反应;使能够
通过创新机制(包括共价交联)与 CA 相互作用。该化合物将是
表征和结构活性关系研究将由 X 射线晶体学、生物物理
研究(延时成像、热位移、组装动力学测定)和病毒学特征
作用机制以及耐药性研究。该研究将由 Stefan 的小组进行
埃默里大学的 Sarafianos(结构、生物物理学、病毒学)和 ZQ Wang(化学合成,埃默里大学)
明尼苏达州)、DRP-NCI 的 Eric Freed(病毒学)以及与 Greg Melikian(成像)合作。
拟议的研究将增进我们对核心稳定性结构基础的理解,核心稳定性控制着
病毒生命周期中的大量步骤。它们还将导致创新化合物先导化合物的识别
具有新颖的“CA 不稳定”作用机制、高效、改进的耐药性、CA 交联
功能,并改善药理特性。
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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Stefan G Sarafianos其他文献
Biochemical mechanism of clinical resistance to rilpivirine
- DOI:
10.1186/1471-2334-12-s1-p94 - 发表时间:
2012-05-04 - 期刊:
- 影响因子:3.000
- 作者:
Kamalendra Singh;Devendra K Rai;Bechan Sharma;Eleftherios Michailidis;Emily M Ryan;Kayla B Matzek;Maxwell D Leslie;Ariel N Hagedorn;Hong-Tao Xu;Mark A Wainberg;Bruno Marchand;Stefan G Sarafianos - 通讯作者:
Stefan G Sarafianos
The Combination of 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine with Rilpivirine Shows Synergistic Anti-HIV-1 Activ- ity In Vitro
4-乙炔基-2-氟-2-脱氧腺苷与利匹韦林的组合在体外显示出协同抗 HIV-1 活性
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
Atsuko Hachiya;Bruno Marchand;Eleftherios Michailidis;Eiichi N Kodama;Michael A Parni- ak;Hiroaki Mitsuya;Shinichi Oka;Stefan G Sarafianos - 通讯作者:
Stefan G Sarafianos
Stefan G Sarafianos的其他文献
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{{ truncateString('Stefan G Sarafianos', 18)}}的其他基金
Discovery of SARS-CoV-2 antivirals using a replicon assay
使用复制子测定发现 SARS-CoV-2 抗病毒药物
- 批准号:
10522048 - 财政年份:2022
- 资助金额:
$ 53.81万 - 项目类别:
Discovery of SARS-CoV-2 antivirals using a replicon assay
使用复制子测定发现 SARS-CoV-2 抗病毒药物
- 批准号:
10673119 - 财政年份:2022
- 资助金额:
$ 53.81万 - 项目类别:
Behavior of HIV in Viral Environments (B-HIVE)
HIV 在病毒环境中的行为 (B-HIVE)
- 批准号:
10650864 - 财政年份:2022
- 资助金额:
$ 53.81万 - 项目类别:
Behavior of HIV in Viral Environments (B-HIVE)
HIV 在病毒环境中的行为 (B-HIVE)
- 批准号:
10508443 - 财政年份:2022
- 资助金额:
$ 53.81万 - 项目类别:
Taking aim at HBV eradication using novel NRTIs and Capsid effectors
使用新型 NRTI 和衣壳效应物消灭 HBV
- 批准号:
9918244 - 财政年份:2017
- 资助金额:
$ 53.81万 - 项目类别:
Ultrapotent Inhibitors of Wild-type and Multi-drug Resistant HIV
野生型和多重耐药艾滋病毒的超强抑制剂
- 批准号:
9605989 - 财政年份:2017
- 资助金额:
$ 53.81万 - 项目类别:
Taking aim at HBV eradication using novel NRTIs and Capsid effectors
使用新型 NRTI 和衣壳效应物消灭 HBV
- 批准号:
9605893 - 财政年份:2017
- 资助金额:
$ 53.81万 - 项目类别:
Reverse Transcriptase Multi-Class Drug Resistance and Rilpivirine Susceptibility in Diverse HIV-1 Subtypes
不同 HIV-1 亚型中的逆转录酶多类耐药性和利匹韦林敏感性
- 批准号:
9140626 - 财政年份:2016
- 资助金额:
$ 53.81万 - 项目类别:
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