Optimizing nucleoside analog efficacy with novel exonuclease inhibitors
使用新型核酸外切酶抑制剂优化核苷类似物的功效
基本信息
- 批准号:10514274
- 负责人:
- 金额:$ 627.12万
- 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:2022-05-16 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoV5&apos-exoribonucleaseAmino Acid SubstitutionAntiviral TherapyBindingBiochemicalBiologicalBiological AssayCOVID-19 treatmentCell Culture TechniquesCellsComplicationConnecticutCoronavirusDNA-Directed RNA PolymeraseDevelopmentDrug ExposureDrug resistanceExcisionExhibitsExonucleaseExoribonucleasesFailureGenerationsGenetic RecombinationGoalsHealth SciencesHepatitis CHepatitis C virusHydrolysisIn VitroIonsLaboratoriesLeadLibrariesMeasuresMessenger RNAMetabolismMetalsMitochondrial RNAMotivationMutagenesisMutationNorth CarolinaNucleosidesNucleotidesOrganOutpatientsPermeabilityPhenotypePolymerasePreventionProductionRNARNA VirusesRNA-Directed RNA PolymeraseResistanceRespiratory SystemSARS-CoV-2 infectionSARS-CoV-2 inhibitorSpecificityStructureStructure-Activity RelationshipTestingTissuesUniversitiesViralViral GenomeViral ProteinsViral Respiratory Tract InfectionVirionVirusVirus Inhibitorsanalogbasecoronavirus therapeuticsdeep sequencingdrug candidatedrug isolationgenomic RNAin vivoinhibitormutantnovelnucleoside analognucleoside triphosphatenucleotide analogpandemic diseasepathogenic virusprogramsreverse geneticsscreeningsingle moleculeviral RNA
项目摘要
Project Abstract
The world is currently under siege by the spread of a novel positive-strand RNA virus, severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2). All positive-strand RNA viruses require their virus-encoded RNA-
dependent RNA polymerase (RdRp) to synthesize RNA to serve as either mRNA for production of viral proteins
or as genomic RNA for progeny virions. Viral polymerases are well-established targets for antiviral therapy with
clear potential for broad-spectrum activity. The RdRp from hepatitis C virus (HCV), another positive-strand RNA
virus, is a key target of the antiviral cocktails developed to cure HCV infection. The most efficacious inhibitors of
viral polymerases with broad-spectrum activity are nucleoside or nucleotide analogs. This class of compounds
binds to the nucleotide substrate-binding pocket of the viral polymerase and is incorporated into nascent RNA,
leading to termination, mutagenesis, or recombination, all of which can be lethal to the virus. Given the conserved
structural and sequence requirements of the nucleotide substrate-binding pocket of viral RdRps, in general, it is
not at all surprising that a nucleotide analog developed to treat one virus would exhibit antiviral activity against
another. Potency in vitro and/or in vivo can differ. The problem in vivo often relates to failure of compound
activation and/or accumulation in the relevant tissue/organ. A coronavirus-specific complication for use of
nucleotide analogs is the presence of a 3’→5’ exoribonuclease activity capable of excising not only mismatched
basepairs but also some antiviral nucleotides. The primary motivation of this project, in alignment with the
Stanford AViDD Center (SyneRx), is development of safe, effective nucleoside/nucleotide candidates for use in
the treatment and/or prevention of SARS CoV-2 infection and perhaps other viral pathogens of the respiratory
system as well. A unique asset of our program is a panel of nucleotide analogs with activity against the SARS-
CoV-2 RdRp discovered by screening a library owned by Riboscience LLC. To increase the potency of these
candidates, we will antagonize excision by inhibiting the exoribonuclease. To achieve these goals we will pursue
the following specific aims: (1) Identify nucleotide analogs for development. (2) Develop strategies to antagonize
the exoribonuclease. (3) Synthesize and characterize ProTides and second-generation nucleotide analogs for
use as anti-coronavirus therapeutics. (4) Biological analysis of polymerase and exoribonuclease inhibitors.
Together, these studies have the potential to discover safe, efficacious nucleotide analogs for use in the
treatment of SARS-CoV-2 infection and perhaps other viral infections of the respiratory system.
项目摘要
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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CRAIG E. CAMERON其他文献
CRAIG E. CAMERON的其他文献
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{{ truncateString('CRAIG E. CAMERON', 18)}}的其他基金
Enteroviral 2C protein as a therapeutic target
肠道病毒2C蛋白作为治疗靶点
- 批准号:
10609524 - 财政年份:2022
- 资助金额:
$ 627.12万 - 项目类别:
Enteroviral 2C protein as a therapeutic target
肠道病毒2C蛋白作为治疗靶点
- 批准号:
10450381 - 财政年份:2022
- 资助金额:
$ 627.12万 - 项目类别:
Contribution of IL-32 gene expression to viral persistence
IL-32 基因表达对病毒持久性的贡献
- 批准号:
10057016 - 财政年份:2020
- 资助金额:
$ 627.12万 - 项目类别:
Contribution of IL-32 gene expression to viral persistence
IL-32 基因表达对病毒持久性的贡献
- 批准号:
10177863 - 财政年份:2020
- 资助金额:
$ 627.12万 - 项目类别:
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