Creation and Validation of cell-based screening systems for SARS-CoV-2 drug targets
SARS-CoV-2 药物靶标细胞筛选系统的创建和验证
基本信息
- 批准号:10618835
- 负责人:
- 金额:$ 19.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-06 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVAmino AcidsAntiviral AgentsAppearanceBiological AssayBiosensorCOVID-19 vaccineCell LineCellsChymaseCodeComplexCoronavirusDevelopmentDisease OutbreaksDoseDrug ScreeningDrug TargetingEconomicsEnzyme InhibitionEnzyme Inhibitor DrugsEnzymesExhibitsFDA approvedFirefly LuciferasesFluorescenceFutureGenomic DNAHealthHumanHydroxychloroquineIndividualInfectionLibrariesLuciferasesLungMessenger RNANational Center for Advancing Translational SciencesPeptide HydrolasesPharmaceutical PreparationsPlasmidsPoint MutationPolyproteinsProteinsRNA Polymerase InhibitorRNA-Directed RNA PolymeraseRecoveryRenilla LuciferasesResearch PersonnelRibonucleic Acid Regulatory SequencesSARS-CoV-2 antiviralSARS-CoV-2 infectionSARS-CoV-2 inhibitorSeriesSiteSystemTestingTherapeuticTransfectionTranslatingUncertaintyUnited States National Institutes of HealthVaccinesValidationViralViral GenomeViral PhysiologyViral ProteinsVirus Diseasesantiviral drug developmentcoronavirus antiviralcoronavirus pandemicdesignenzyme activityexpression vectorimprovedin vitro activityinhibitornovel coronavirusred fluorescent proteinresistant strainresponsescreeningscreening programstable cell linevaccine acceptancevectorzoonotic coronavirus
项目摘要
Project Summary/Abstract:
Effective antivirals are sorely needed against SARS CoV-2 (CoV2), and coronaviruses (CoV) in
general. Screening systems for drugs targeting CoV2 enzymes usually involve screening against
purified enzymes. This can be technically challenging, and the vast majority of inhibitors identified
ultimately lack utility as antivirals because: they may not be transported into and retained in cells,
altered within cells such that they no longer inhibit the target effectively, or exhibit off-target effects that
preclude their use as therapeutics. Using predicted drugs directly in viral infection assays can exhibit
off-target effects against the host cell or other viral proteins and can be difficult to distinguish within the
context of the viral infection (the inhibition of CoV2 infection by hydroxychloroquine is one such
example). Ideally screens for viral enzymes isolate the enzyme from the viral infection, but evaluate
function within human cells. We have constructed vectors for expression of four wild-type CoV2
proteins, and unique biosensors, to evaluate function of two CoV2 enzymatic functions, the CoV Main
Protease and the CoV RNA-dependent RNA polymerase complex. We are completing assay validation
and beginning to use the assays to evaluate the few known inhibitors of these enzymes. The protease
assay will be converted to a stable cell line for large scale screening programs. The transfection assays
will be evaluated using both established and experimental 3CL and RdRpC inhibitors, and 128 FDA-
approved drugs that we have predicted target these enzymes, to validate the usefulness of these
screening assays. Drugs that show inhibition of activity will be quantified using dose-response analysis
in the cell-based assays, and subsequently analyzed for inhibition of CoV2 infection of cultured human
lung cells across a similar dose-response range. Following validation, vectors and/or stable cells lines
for the cell-based drug screening systems will be made readily available to other researchers, such as
NIH’s NCATS, who are currently seeking CoV antiviral agents.
项目总结/文摘:
项目成果
期刊论文数量(0)
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会议论文数量(0)
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THOMAS MELENDY的其他文献
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{{ truncateString('THOMAS MELENDY', 18)}}的其他基金
Creation and Validation of cell-based screening systems for SARS-CoV-2 drug targets
SARS-CoV-2 药物靶标细胞筛选系统的创建和验证
- 批准号:
10373681 - 财政年份:2022
- 资助金额:
$ 19.94万 - 项目类别:
Slowing of the polyomavirus DNA replication fork in response to DDR
DDR 导致多瘤病毒 DNA 复制叉减慢
- 批准号:
10408848 - 财政年份:2021
- 资助金额:
$ 19.94万 - 项目类别:
Slowing of the polyomavirus DNA replication fork in response to DDR
DDR 导致多瘤病毒 DNA 复制叉减慢
- 批准号:
10289169 - 财政年份:2021
- 资助金额:
$ 19.94万 - 项目类别:
Evaluation and development of E1-TopoI as a target for anti-HPV therapeutics
E1-TopoI 作为抗 HPV 治疗靶点的评估和开发
- 批准号:
8297142 - 财政年份:2012
- 资助金额:
$ 19.94万 - 项目类别:
Evaluation and development of E1-TopoI as a target for anti-HPV therapeutics
E1-TopoI 作为抗 HPV 治疗靶点的评估和开发
- 批准号:
8450078 - 财政年份:2012
- 资助金额:
$ 19.94万 - 项目类别:
Evaluation and development of E1-TopoI as a target for anti-HPV therapeutics
E1-TopoI 作为抗 HPV 治疗靶点的评估和开发
- 批准号:
8638888 - 财政年份:2012
- 资助金额:
$ 19.94万 - 项目类别:
MECHANISMS OF DNA DAMAGE TRIGGERED S PHASE CHECKPOINTS
DNA 损伤触发 S 相检查点的机制
- 批准号:
6833488 - 财政年份:2001
- 资助金额:
$ 19.94万 - 项目类别:
MECHANISMS OF DNA DAMAGE TRIGGERED S PHASE CHECKPOINTS
DNA 损伤触发 S 相检查点的机制
- 批准号:
6626784 - 财政年份:2001
- 资助金额:
$ 19.94万 - 项目类别:
MECHANISMS OF DNA DAMAGE TRIGGERED S PHASE CHECKPOINTS
DNA 损伤触发 S 相检查点的机制
- 批准号:
6229425 - 财政年份:2001
- 资助金额:
$ 19.94万 - 项目类别:
MECHANISMS OF DNA DAMAGE TRIGGERED S PHASE CHECKPOINTS
DNA 损伤触发 S 相检查点的机制
- 批准号:
6692971 - 财政年份:2001
- 资助金额:
$ 19.94万 - 项目类别:
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