A Method to Stop HIV Replication:Inhibition of Human Purine Utilizing Proteins
阻止HIV复制的方法:抑制人嘌呤利用蛋白
基本信息
- 批准号:8457221
- 负责人:
- 金额:$ 1.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-06-01 至 2013-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAmino AcidsAntineoplastic AgentsAntiviral AgentsAttenuatedBacterial InfectionsBindingBinding ProteinsBiologyCD4 Positive T LymphocytesCell Culture TechniquesCellsClinical TrialsCommunicable DiseasesCoupledDNADatabasesDevelopmentDown-RegulationDrug Delivery SystemsDrug resistanceEnzymesErectile dysfunctionEventFundingGenerationsGeneric DrugsGoalsHIVHIV InfectionsHIV drug resistanceHIV-1Heat shock proteinsHumanHypertensionInfectionJurkat CellsLeadLife Cycle StagesLinkMalignant NeoplasmsMass Spectrum AnalysisMethodsModelingMonomeric GTP-Binding ProteinsNADHNon-Insulin-Dependent Diabetes MellitusOnline Mendelian Inheritance In ManOxidoreductasePathway interactionsPharmaceutical PreparationsPhasePlant ResinsPredispositionProcessProtein BindingProtein KinaseProteinsProteomeProteomicsPurinesRNA chemical synthesisRegulationResearchResistance developmentRetroviridaeReverse TranscriptionRoleSmall Interfering RNAStable Isotope LabelingSystemTRIM GeneTechnologyTherapeuticTimeTranscription ProcessVaccinesValidationVertebral columnViralViral ProteinsVirusWolvesWorkbaseconventional therapydesigndrug discoveryexperiencefunctional genomicshelicasehuman diseasehypercholesterolemiainnovationinnovative technologiesmacrophagemicrobicidemonocytenovelnovel strategiespandemic diseaseprotein activationprotein expressionprotein foldingpurinesmall moleculetherapeutic targettissue culturetissue/cell culture
项目摘要
DESCRIPTION (provided by applicant):
Owing to the recent setbacks in vaccine and microbicide trails, novel strategies to slow the HIV-pandemic are desperately needed. Development of a small molecule that blocked a host process required for HIV-1 replication could provide such a strategy. Like all retroviruses, HIV-1 requires host proteins to complete its life cycle, and these intracellular host molecules represent an undeveloped pool of novel anti-HIV therapeutics. The goal of this application is to use functional proteomics to identify host proteins that are dispensable to the host but essential for viral replication. A generic proteomic screen would likely identify numerous host proteins induced by HIV-infection, most of which would be poor therapeutic candidates. A functional proteomics screen, which queries a subset of proteins with strong therapeutic potential, would greatly simplify the search for host targets; the host purinome has this potential. The purinome comprises any protein that binds purine- containing molecules (e.g. ATP, NADH), and it includes heat shock proteins, dehydrogenases, and protein kinases. Inhibition of purinome proteins forms the basis of many current therapies, including those targeting cancer, hypertension, and bacterial infections. The central hypothesis of this application states that inhibition of purinome proteins, which are induced or regulated by HIV-infection, will block HIV-1 replication. Our research team has designed a protein affinity media that captures the entire purinome through its purine-binding pocket. The proposed research will proceed in four broad steps: use SILAC (stable isotope labeling with amino acids in cell culture) to quantify purinome proteins induced by HIV-1 infection of THP1 and Jurkat cells (target identification); determine which purinome proteins are essential for HIV-1 replication (target validation); identify drugs that selectively compete validated targets from the purinome-binding resin (drug discovery); confirm that these compounds block HIV-replication in primary cells (drug validation). During this process, we will also identify host proteins that interact with HIV-1, and in the event that a viable purinome target and/or drug is not identified, viral biology will be advanced by a greater understanding of how HIV-1 interacts with its host. The proposed research uses innovative proteomics technology (SILAC) and an unconventional, yet validated, approach. First, conventional anti-HIV therapeutics inhibit virally-encoded proteins, which makes them more susceptible to the development of resistance. By targeting a host enzyme that is required for HIV-1 replication, it is likely that the virus will have to undergo more radical changes to offset the changes in the host milieu. Second, conventional drug discovery uses a reductionist approach to separately identify a target and a drug, while our approach combines the target/drug identification process, which makes discovery more efficient. At the completion of this project, our combination of experience and technology will enable us to characterize host purine-binding proteins that are essential for HIV-1 replication and identify several lead compounds that will inhibit host proteins necessary for HIV-1 replication.
描述(由申请人提供):
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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{{ truncateString('JESSE J KWIEK', 18)}}的其他基金
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HIV/ART、低出生体重和暴露于 HIV 的未感染儿童的死亡率:一项转化机制研究
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10393702 - 财政年份:2021
- 资助金额:
$ 1.33万 - 项目类别:
HIV/ART, low birth weight, and mortality in HIV-exposed uninfected children: a translational mechanistic study
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10614479 - 财政年份:2021
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$ 1.33万 - 项目类别:
HIV/ART, low birth weight, and mortality in HIV-exposed uninfected children: a translational mechanistic study
HIV/ART、低出生体重和暴露于 HIV 的未感染儿童的死亡率:一项转化机制研究
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10258233 - 财政年份:2021
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De novo fatty acid biosynthesis and HIV replication
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- 批准号:
10190804 - 财政年份:2020
- 资助金额:
$ 1.33万 - 项目类别:
De novo fatty acid biosynthesis and HIV replication
从头脂肪酸生物合成和 HIV 复制
- 批准号:
10082548 - 财政年份:2020
- 资助金额:
$ 1.33万 - 项目类别:
A Method to Stop HIV Replication:Inhibition of Human Purine Utilizing Proteins
阻止HIV复制的方法:抑制人嘌呤利用蛋白
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7984177 - 财政年份:2010
- 资助金额:
$ 1.33万 - 项目类别:
A Method to Stop HIV Replication:Inhibition of Human Purine Utilizing Proteins
阻止HIV复制的方法:抑制人嘌呤利用蛋白
- 批准号:
8468988 - 财政年份:2010
- 资助金额:
$ 1.33万 - 项目类别:
A Method to Stop HIV Replication:Inhibition of Human Purine Utilizing Proteins
阻止HIV复制的方法:抑制人嘌呤利用蛋白
- 批准号:
8075457 - 财政年份:2010
- 资助金额:
$ 1.33万 - 项目类别:
A Method to Stop HIV Replication:Inhibition of Human Purine Utilizing Proteins
阻止HIV复制的方法:抑制人嘌呤利用蛋白
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- 资助金额:
$ 1.33万 - 项目类别:
Viral and Placental Determinants of HIV-1 Subtype C Mother-to-Child Transmission
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7223672 - 财政年份:2007
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