Exploring herpesvirus exonucleases as potential antiviral targets

探索疱疹病毒核酸外切酶作为潜在的抗病毒靶点

基本信息

项目摘要

Over 90% of the world’s population is seropositive for three or more of the nine human herpesviruses (HHVs), which possess the ability to establish lifelong latent infections that can be reactivated. Reactivation of HHV infections is particularly serious in immunocompromised patients leading to disseminated life-threatening infections. Although many of the anti HHV drug discovery efforts to date have focused on nucleoside/tide HHV polymerase inhibitors, the large number of essential replication proteins encoded by the herpesviruses provide excellent novel targets for antiviral therapy. New agents are needed to better prevent pathological sequelae of reactivation as well as viral shedding and transmission to new hosts. The need for new modalities of therapeutics to treat HHV infections underscores the importance of a more thorough understanding of HHV DNA replication. In addition to the seven essential herpes simplex virus (HSV) replication proteins identified by us and others, we have shown that the viral alkaline nuclease UL12 is also essential for the production of viral DNA that can be packaged into infectious virus. UL12 interacts with the HSV ssDNA binding protein ICP8 to form a two-component recombinase (exo/SSAP) that can promote single strand annealing (SSA). We have suggested that HSV uses an unusual mechanism of DNA replication that has more in common with bacteriophage than eukaryotic cells or other eukaryotic viruses. In fact, all DNA viruses of bacteria, protozoa, plants, insects and mammals that replicate through concatemer formation encode a similar exo/SSAP complex. We hypothesize that ICP8 and UL12 promote a series of reactions in which UL12 resects dsDNA leaving a 3’ ssDNA overhang that is recognized by ICP8. ICP8 then promotes annealing of the ssDNA to an active replication fork to promote DNA synthesis by the viral DNA polymerase (UL30). UL30 is comprised of two functional domains: a 3’ to 5’ exonuclease, PolExo, that plays a role in proofreading and the catalytic polymerase domain required for extending primers during viral DNA replication. While the SSA model for DNA replication is consistent with available evidence, questions remain about how UL12 and the two activities of the polymerase function during DNA synthesis. In parallel studies, the Wright and Weller labs have been interested in both AN and PolExo and their othologs from other HHVs as targets for novel antiviral therapeutics and have generated focused libraries designed for their ability to engage a two-metal binding motif found in both AN and PolExo active sites. We have identified several lead compounds that are potent antivirals and inhibit one or more of the exonuclease activities and in some cases additional activity against polymerase activity itself. In this proposal we will use our lead compounds as molecular probes to study mechanisms of viral DNA replication and to continue our efforts to develop broad spectrum antiviral agents that inhibit AN, PolExo and/or Pol. Agents that can inhibit more than one of these targets would be expected to increase the barrier to antiviral drug resistances.
世界上超过 90% 的人口对九种人类疱疹病毒 (HHV) 中的三种或三种以上呈血清反应阳性, 它具有建立可重新激活的终生潜伏感染的能力。 HHV 重新激活 感染在免疫功能低下的患者中尤其严重,导致播散性危及生命 感染。尽管迄今为止许多抗 HHV 药物发现工作都集中在核苷/潮汐 HHV 上 聚合酶抑制剂,由疱疹病毒编码的大量必需复制蛋白 为抗病毒治疗提供了优异的新靶点。需要新的药物来更好地预防病理性 重新激活以及病毒脱落和传播给新宿主的后遗症。需要新的模式 治疗 HHV 感染的疗法强调了更彻底了解 HHV 的重要性 DNA复制。除了 7 种必需的单纯疱疹病毒 (HSV) 复制蛋白外, 我们和其他人已经证明,病毒碱性核酸酶 UL12 对于病毒的生产也是必不可少的 可包装成传染性病毒的DNA。 UL12 与 HSV ssDNA 结合蛋白 ICP8 相互作用, 形成可以促进单链退火(SSA)的双组分重组酶(exo/SSAP)。我们有 表明 HSV 使用一种不寻常的 DNA 复制机制,该机制与 噬菌体比真核细胞或其他真核病毒更重要。事实上,细菌、原生动物、 通过多联体形成复制的植物、昆虫和哺乳动物编码类似的 exo/SSAP 复合物。 我们假设 ICP8 和 UL12 促进了一系列反应,其中 UL12 切除 dsDNA,留下 3’ ICP8 识别的 ssDNA 突出端。然后 ICP8 促进 ssDNA 退火至主动复制 叉促进病毒 DNA 聚合酶 (UL30) 的 DNA 合成。 UL30 由两个功能组成 结构域:一种 3' 至 5' 核酸外切酶 PolExo,在校对和催化聚合酶结构域中发挥作用 病毒 DNA 复制期间延伸引物所需的。虽然 DNA 复制的 SSA 模型是一致的 根据现有证据,关于 UL12 和聚合酶的两种活性如何发挥作用的问题仍然存在 DNA合成过程中。在并行研究中,Wright 和 Weller 实验室对 AN 和 PolExo 都感兴趣 及其来自其他 HHV 的同源物作为新型抗病毒疗法的靶标,并产生了集中的 文库的设计目的是能够接合 AN 和 PolExo 活性位点中发现的双金属结合基序。 我们已经鉴定出几种先导化合物,它们是有效的抗病毒药物并抑制一种或多种核酸外切酶 活性以及在某些情况下针对聚合酶活性本身的额外活性。在这个提案中我们将使用 我们的先导化合物作为分子探针来研究病毒 DNA 复制机制并继续 我们致力于开发抑制 AN、PolExo 和/或 Pol 的广谱抗病毒药物。代理可以 抑制这些靶标中的一个以上预计会增加抗病毒药物耐药性的障碍。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

SANDRA K WELLER其他文献

SANDRA K WELLER的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('SANDRA K WELLER', 18)}}的其他基金

Exploring the Coronavirus Exoribonuclease as an Antiviral Target
探索冠状病毒外核糖核酸酶作为抗病毒靶点
  • 批准号:
    10238324
  • 财政年份:
    2021
  • 资助金额:
    $ 60.53万
  • 项目类别:
Genetics of HSV DNA Replication
HSV DNA 复制的遗传学
  • 批准号:
    8631838
  • 财政年份:
    2013
  • 资助金额:
    $ 60.53万
  • 项目类别:
New faculty recruitment in NMR structural biology
核磁共振结构生物学新教师招聘
  • 批准号:
    7857166
  • 财政年份:
    2009
  • 资助金额:
    $ 60.53万
  • 项目类别:
New faculty recruitment in NMR structural biology
核磁共振结构生物学新教师招聘
  • 批准号:
    7944151
  • 财政年份:
    2009
  • 资助金额:
    $ 60.53万
  • 项目类别:
ASM Conference on Manipulation of Nuclear Processes by DNA Viruses
ASM DNA 病毒操纵核过程会议
  • 批准号:
    7485476
  • 财政年份:
    2008
  • 资助金额:
    $ 60.53万
  • 项目类别:
Role of viral and cellular recombination proteins in HSV DNA replication
病毒和细胞重组蛋白在 HSV DNA 复制中的作用
  • 批准号:
    7548622
  • 财政年份:
    2006
  • 资助金额:
    $ 60.53万
  • 项目类别:
Role of viral and cellular recombination proteins in HSV DNA replication
病毒和细胞重组蛋白在 HSV DNA 复制中的作用
  • 批准号:
    8610869
  • 财政年份:
    2006
  • 资助金额:
    $ 60.53万
  • 项目类别:
Role of viral and cellular recombination proteins in HSV DNA replication
病毒和细胞重组蛋白在 HSV DNA 复制中的作用
  • 批准号:
    8438424
  • 财政年份:
    2006
  • 资助金额:
    $ 60.53万
  • 项目类别:
Role of viral and cellular recombination proteins in HSV DNA replication
病毒和细胞重组蛋白在 HSV DNA 复制中的作用
  • 批准号:
    7079573
  • 财政年份:
    2006
  • 资助金额:
    $ 60.53万
  • 项目类别:
Role of viral and cellular recombination proteins in HSV DNA replication
病毒和细胞重组蛋白在 HSV DNA 复制中的作用
  • 批准号:
    7338346
  • 财政年份:
    2006
  • 资助金额:
    $ 60.53万
  • 项目类别:

相似海外基金

Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
  • 批准号:
    2334970
  • 财政年份:
    2024
  • 资助金额:
    $ 60.53万
  • 项目类别:
    Standard Grant
NSF-BSF: Towards a Molecular Understanding of Dynamic Active Sites in Advanced Alkaline Water Oxidation Catalysts
NSF-BSF:高级碱性水氧化催化剂动态活性位点的分子理解
  • 批准号:
    2400195
  • 财政年份:
    2024
  • 资助金额:
    $ 60.53万
  • 项目类别:
    Standard Grant
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
  • 批准号:
    2334969
  • 财政年份:
    2024
  • 资助金额:
    $ 60.53万
  • 项目类别:
    Standard Grant
Mechanochemical synthesis of nanocarbon and design of active sites for oxygen reducton/evolution reactions
纳米碳的机械化学合成和氧还原/演化反应活性位点的设计
  • 批准号:
    23K04919
  • 财政年份:
    2023
  • 资助金额:
    $ 60.53万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Creation of porous inorganic frameworks with controlled structure of metal active sites by the building block method.
通过积木法创建具有金属活性位点受控结构的多孔无机框架。
  • 批准号:
    22KJ2957
  • 财政年份:
    2023
  • 资助金额:
    $ 60.53万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Catalysis of Juxaposed Active Sites Created in Nanospaces and Their Applications
纳米空间中并置活性位点的催化及其应用
  • 批准号:
    23K04494
  • 财政年份:
    2023
  • 资助金额:
    $ 60.53万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Generation of carbon active sites by modifying the oxygen containing functional groups and structures of carbons for utilizing to various catalytic reactions.
通过修饰碳的含氧官能团和结构来产生碳活性位点,用于各种催化反应。
  • 批准号:
    23K13831
  • 财政年份:
    2023
  • 资助金额:
    $ 60.53万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
CAREER: CAS: Understanding the Chemistry of Palladium and Silyl Compounds to Design Catalyst Active Sites
职业:CAS:了解钯和甲硅烷基化合物的化学性质以设计催化剂活性位点
  • 批准号:
    2238379
  • 财政年份:
    2023
  • 资助金额:
    $ 60.53万
  • 项目类别:
    Continuing Grant
CAS: Collaborative Research: Tailoring the Distribution of Transient vs. Dynamic Active Sites in Solid-Acid Catalysts and Their Impacts on Chemical Conversions
CAS:合作研究:定制固体酸催化剂中瞬时活性位点与动态活性位点的分布及其对化学转化的影响
  • 批准号:
    2154399
  • 财政年份:
    2022
  • 资助金额:
    $ 60.53万
  • 项目类别:
    Standard Grant
Engineering of Active Sites in Heterogeneous Catalysts for Sustainable Chemical and Fuel Production.
用于可持续化学和燃料生产的多相催化剂活性位点工程。
  • 批准号:
    RGPIN-2019-06633
  • 财政年份:
    2022
  • 资助金额:
    $ 60.53万
  • 项目类别:
    Discovery Grants Program - Individual
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了