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

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:
Core C: Enzymology Core
核心 C:酶学核心
  • 批准号:
    10513682
  • 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:
Picornavirus Genome Replication
小核糖核酸病毒基因组复制
  • 批准号:
    10021287
  • 财政年份:
    2019
  • 资助金额:
    $ 627.12万
  • 项目类别:
RNA-dependent RNA Polymerase
RNA依赖性RNA聚合酶
  • 批准号:
    10017543
  • 财政年份:
    2019
  • 资助金额:
    $ 627.12万
  • 项目类别:
Picornavirus Genome Replication
小核糖核酸病毒基因组复制
  • 批准号:
    10640512
  • 财政年份:
    2019
  • 资助金额:
    $ 627.12万
  • 项目类别:
Picornavirus Genome Replication
小核糖核酸病毒基因组复制
  • 批准号:
    10447359
  • 财政年份:
    2019
  • 资助金额:
    $ 627.12万
  • 项目类别:
Picornavirus Genome Replication
小核糖核酸病毒基因组复制
  • 批准号:
    10331323
  • 财政年份:
    2019
  • 资助金额:
    $ 627.12万
  • 项目类别:

相似国自然基金

晚期妊娠维持和抑制早产中cAMP信号活化PR的作用机制研究
  • 批准号:
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  • 批准年份:
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