A New Paradigm for HIV Treatment: Targeted Degradation of HIV Reverse Transcriptase via the Ubiquitin-Proteasome Pathway
HIV 治疗的新范式:通过泛素-蛋白酶体途径靶向降解 HIV 逆转录酶
基本信息
- 批准号:10153409
- 负责人:
- 金额:$ 20.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-11-06 至 2022-10-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAntineoplastic AgentsAntiviral AgentsBindingBiological AssayBiological AvailabilityBiologyCD4 Positive T LymphocytesChronicClinicClinicalClinical TreatmentClinical TrialsCommunicable DiseasesComplexComputing MethodologiesDBL OncoproteinDetectionDevelopmentDiseaseDrug resistanceEnhancersEpidemicFoundationsFutureGenetic VariationGoalsHIVHIV InfectionsHIV resistanceHIV-1Hepatitis C virusImpairmentInfectionLeadLigandsMaintenance TherapyMalignant NeoplasmsMediatingModalityModelingMolecular ConformationMutationMycobacterium tuberculosisOralOrganic SynthesisOutcomePathway interactionsPatientsPeptide HydrolasesPharmaceutical ChemistryPharmaceutical PreparationsPharmacotherapyPredispositionPreparationPreventionProbabilityPropertyProteinsRNA-Directed DNA PolymeraseReagentRegimenReportingRequest for ApplicationsResearchResistanceResistance developmentReverse Transcriptase InhibitorsSavingsSeriesSiteStructureTherapeuticTherapeutic InterventionTreatment FailureTreatment outcomeUbiquitinUbiquitinationUnited States National Institutes of HealthVariantViralVirus DiseasesVirus Replicationanaloganti-cancerantimicrobial drugantiretroviral therapyassay developmentbasecompliance behaviordesigndrug developmentdrug discoveryexperiencefight againsthigh rewardhigh riskin vitro Modelin vivoinhibitor/antagonistmulticatalytic endopeptidase complexnew technologynon-nucleoside reverse transcriptase inhibitorsnovel therapeutic interventionnovel therapeuticspre-exposure prophylaxispreventprogramsprotein degradationprotein functionprototyperecruitresistant strainscreeningsimulationubiquitin-protein ligaseviral resistance
项目摘要
PROJECT SUMMARY/ABSTRACT
In accordance with RFA-AI-19-072, Novel Therapeutics Directed to Intracellular HIV Targets, we propose using
targeted protein degradation (TPD) against the essential HIV reverse transcriptase (RT). The RFA states
“Controlling protein function by controlling intracellular protein levels has evolved as a promising and novel
therapeutic strategy. This can be achieved by the targeted degradation of intracellular proteins thru the ubiquitin-
proteasome pathway.” Heterobifunctional targeted protein degraders (TPDs) are being actively pursued as
enhancers of proteasomal destruction of proteins specifically associated with several cancers. Such agents offer
advantages over traditional occupancy-based inhibitors including a unique catalytic mechanism of action, greater
target selectivity, and a reduced probability for resistance development. Surprisingly, this promising therapeutic
modality has only recently been applied to antiviral drug discovery through a successful Telapravir-based TPD
effective against the wild type and resistant forms of the HCV protease. Analysis of reported HIV-1 drug-bound
structures suggests that the essential viral RT should be readily adaptable to targeted protein degradation. The
potent and clinically used HIV-1 RT inhibitor (RTI), Rilpivirine (RPV) binds the RT site in Gag-Pol and also
allosterically inhibits p66/p51 RT function by binding the non-nucleoside-RTI (NNRTI) Binding Pocket
(NNIBP) on the p66 subunit. RPV is amenable to conjugation with linkers and ubiquitin E3 ligase recruiting
ligands to serve in the design and preparation of prototype HIV-1 RT TPDs. The OBJECTIVE of this study is to
show proof-of-concept of a new inhibitory mechanism by which HIV-1 RT can be targeted for degradation,
impairing HIV infectivity and replication. Importantly, due to TPDs’ unique mechanism of action, even a low-
affinity RT/TPD interaction will likely lead to effective target degradation. Thus, we pose the HYPOTHESIS that
RPV-based TPDs will not only augment inhibition against HIV-1 with RTI-sensitive RT but will remain effective
against RTI-resistant RT variants. Ultimately, this approach can reduce resistance development and potentially
extend regimen lifetimes in the fight against HIV disease. The objective of AIM 1 is to design and prepare RPV-
based TPDs built on state-of-the-art computational methods and predictive physicochemical properties currently
accepted for in vivo active TPDs. In AIM 2, we will screen the two series of TPDs for antiviral activity in
complementary in vitro models of HIV-1 single-round infection (in the TZM-bl assay), and of replication (in primary
CD4+ T lymphocytes). The IMPACT of the discovery of targeted HIV-1 RT degraders that limit infectivity and
replication through a mechanism distinct from occupancy-based HIV-1 RTIs will be the identification of agents
that are effective against RTI-resistant HIV strains and that limit RTI susceptibility to viral resistance
development. Grandly, this research will demonstrate that TPD approaches can be superior in the treatment of
HIV disease and will set the stage for the advancement of TPDs against other HIV targets with improvements in
the prevention of resistance development and with concomitant enhanced clinical treatment outcomes.
项目摘要/摘要
根据RFA-AI-19-072,针对细胞内HIV靶点的新型治疗药物,我们建议使用
针对基本的HIV逆转录酶的靶向蛋白质降解(TPD)。RFA声明
通过控制细胞内蛋白质水平来控制蛋白质功能已经成为一种很有前途的新方法。
治疗策略。这可以通过对细胞内蛋白质的靶向降解来实现,通过泛素-
蛋白酶体途径。异双功能靶向蛋白降解物(TPDs)作为一种新的靶向蛋白降解物正受到人们的广泛关注
蛋白酶体破坏与几种癌症相关的蛋白质的增强剂。这样的代理商提供
与传统的基于占有率的缓蚀剂相比,优势包括独特的催化作用机理,更大
靶标选择性,并降低了抗药性发展的可能性。令人惊讶的是,这种有希望的治疗方法
最近才通过基于Telapravir的TPD成功地将这种方法应用于抗病毒药物的发现
对野生型和抗性形式的丙型肝炎病毒蛋白酶有效。报告的HIV-1药物结合情况分析
结构表明,基本的病毒RT应该很容易适应靶向的蛋白质降解。这个
强效的临床使用的HIV-1逆转录酶抑制剂(RTI)利培韦林(RPV)可结合Gag-Pol中的RT位点,还
通过结合非核苷-RTI(NNRTI)结合口袋变构抑制p66/p51 RT功能
(NNIBP)在p66亚基上。RPV可与接头和泛素E3连接酶结合
用于设计和制备HIV-1 RT TPD原型的配体。这项研究的目的是
展示了一种新的抑制机制的概念验证,通过这种机制,HIV-1RT可以被靶向降解,
削弱艾滋病毒的传染性和复制能力。重要的是,由于TPD独特的作用机制,即使是低成本的
亲和RT/TPD相互作用可能导致有效的靶标降解。因此,我们假设
基于RPV的TPD不仅将通过RTI敏感RT增强对HIV-1的抑制,而且将保持有效
抵抗RTI的RT变异体。最终,这种方法可以减少耐药性的发展,并有可能
在与艾滋病毒疾病的斗争中延长方案的寿命。AIM 1的目标是设计和制备RPV-
基于目前最先进的计算方法和预测物理化学性质的TPD
接受体内活性TPD。在AIM 2中,我们将对两个系列的TPD进行抗病毒活性筛选
互补的HIV-1单轮感染(在TZM-bl试验中)和复制(在原代)的体外模型
CD4+T淋巴细胞)。靶向HIV-1 RT降解物的发现对限制传染性和
通过一种不同于基于占有率的HIV-1 RTI的机制进行复制将是对病原体的识别
对耐RTI的HIV毒株有效,并限制RTI对病毒耐药性的敏感性
发展。更重要的是,这项研究将证明TPD方法在治疗慢性阻塞性肺疾病方面具有优势。
并将为TPD相对于其他艾滋病毒目标取得进展奠定基础,在
预防耐药性的发展,并伴随着提高临床治疗结果。
项目成果
期刊论文数量(0)
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Robert C Reynolds其他文献
Robert C Reynolds的其他文献
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{{ truncateString('Robert C Reynolds', 18)}}的其他基金
A New Paradigm for HIV Treatment: Targeted Degradation of HIV Reverse Transcriptase via the Ubiquitin-Proteasome Pathway
HIV 治疗的新范式:通过泛素-蛋白酶体途径靶向降解 HIV 逆转录酶
- 批准号:
10299633 - 财政年份:2020
- 资助金额:
$ 20.54万 - 项目类别:
Pilot-Scale Libraries Based on Nucleoside Templates for the ML Initiative
用于 ML 计划的基于核苷模板的中试规模文库
- 批准号:
7683197 - 财政年份:2008
- 资助金额:
$ 20.54万 - 项目类别:
Pilot-Scale Libraries Based on Nucleoside Templates for the ML Initiative
用于 ML 计划的基于核苷模板的中试规模文库
- 批准号:
7938009 - 财政年份:2008
- 资助金额:
$ 20.54万 - 项目类别:
Pilot-Scale Libraries Based on Nucleoside Templates for the ML Initiative
用于 ML 计划的基于核苷模板的中试规模文库
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7556025 - 财政年份:2008
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Mtb 半乳糖基转移酶的结晶
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Inhibitor of FtsZ Polymerization in M. tuberculosis
结核分枝杆菌中 FtsZ 聚合的抑制剂
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6751274 - 财政年份:2002
- 资助金额:
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Inhibitor of FtsZ Polymerization in M. tuberculosis
结核分枝杆菌中 FtsZ 聚合的抑制剂
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6496584 - 财政年份:2002
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Inhibitor of FtsZ Polymerization in M. tuberculosis
结核分枝杆菌中 FtsZ 聚合的抑制剂
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6627839 - 财政年份:2002
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