Towards the Disruption of Viral RNA Replication

致力于破坏病毒 RNA 复制

基本信息

  • 批准号:
    8341918
  • 负责人:
  • 金额:
    $ 36.01万
  • 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:
    2012-07-01 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Diseases caused by positive-sense single-stranded RNA viruses, including poliovirus, rhinovirus, hepatitis C virus, and SARS, are critical health issues worldwide. Progression of disease requires replication of the virus genome by oligomeric complexes assembled on virally-induced membrane structures in the host cell. Design of drugs that interfere with protein-protein interactions has made considerable progress in recent years, making disruption of the viral replication complex an attractive target for antiviral intervention. This proposal focuses on poliovirus (i) in order to use the extensive knowledge of the structural and functional properties of poliovirus as a basis for detailed characterization of these protein-protein interactions, and (ii) to address the need for new antiviral strategies against poliovirus that a 2007 National Academy of Sciences panel asserted would significantly strengthen the eradication effort, and prevent its threat as a bioweapon against an unvaccinated population. Assemblies of poliovirus RNA polymerase, the functional centerpiece of the replication complex, will be analyzed in terms of the intermolecular interactions responsible for their stability and interpreted on the basis of high resolution crystallographic data and extensive mutational and biochemical data. As the field of structural electron microscopy advances toward routine sub-nanometer resolution, it is biological questions such as those asked here that continue to motivate technical innovations. In Specific Aim 1, methods for the routine use of cryo-electron microscopy to solve structures of nanocrystals as small as 10 unit cells on a side will be developed and used to analyze the structure of nanocrystals of RNA polymerase and characterize the intermolecular interactions therein. This will be of value far beyond the proposed studies of polymerase, enabling structural analyses of the 'shower' of protein nanocrystals that often appear in crystallization trays, that until now have been discarded as failed experiments, and that recently have been attracting greatly increased interest. In Specific Aim 2, a mechanism for stabilizing polymerase-RNA complexes and supporting RNA replication via a positively charged channel across the polymerase interface will be tested by structural and functional analyses of complexes comprising wild-type and mutant polymerases. In Specific Aim 3 transfection of viral replication proteins into mammalian cells will be used to (i) define th minimum viral component required for the membrane reorganization of cellular membrane into double-bilayers, and (ii) characterize the protein-protein interactions that stabilize polymerase-containing oligomers, as these interfaces represent sites of vulnerability for disruption of viral replication and for development as potential drug targets. PUBLIC HEALTH RELEVANCE: New antiviral medications against poliovirus and similar viruses, such as hepatitis C and SARS, are needed to treat patients with these diseases, and to help prevent the threat of their use as a bioweapon against an unvaccinated population. A promising approach is to target the proteins needed for the virus to make new copies of itself. The proposed research will look at assemblies formed by the proteins that are essential for copying the virus gene, and locate vulnerable regions for future drug design.
描述(由申请人提供):由正义单链RNA病毒(包括脊髓灰质炎病毒、鼻病毒、丙型肝炎病毒和SARS)引起的疾病是全球范围内的重大健康问题。疾病的进展需要通过在宿主细胞中病毒诱导的膜结构上组装的寡聚复合物来复制病毒基因组。近年来,干扰蛋白质-蛋白质相互作用的药物设计取得了相当大的进展,使得破坏病毒复制复合物成为抗病毒干预的有吸引力的靶点。 该提案重点关注脊髓灰质炎病毒,(i)为了利用脊髓灰质炎病毒结构和功能特性的广泛知识作为这些蛋白质-蛋白质相互作用的详细表征的基础,(ii)解决针对脊髓灰质炎病毒的新抗病毒策略的需求,2007年美国国家科学院小组断言将大大加强根除工作,并防止其作为生物武器对未接种疫苗的人群造成威胁。 脊髓灰质炎病毒RNA聚合酶的组装,复制复合物的功能中心,将进行分析的分子间相互作用,负责其稳定性和解释的基础上,高分辨率的晶体学数据和广泛的突变和生化数据。随着结构电子显微镜领域向常规亚纳米分辨率的发展,生物学问题(如本文所问的问题)继续推动技术创新。在具体目标1中,将开发用于常规使用冷冻电子显微镜来解析一侧上小至10个单位细胞的纳米晶体的结构的方法,并用于分析RNA聚合酶的纳米晶体的结构并表征其中的分子间相互作用。这将是远远超出聚合酶的拟议研究的价值,使结构分析的“淋浴”的蛋白质纳米晶体,经常出现在结晶托盘,到目前为止已被丢弃的失败的实验,最近已经吸引了极大的兴趣。在特定 目的2,用于稳定聚合酶-RNA复合物和支持RNA复制的机制,通过跨聚合酶界面的带正电荷的通道将通过包含野生型和突变聚合酶的复合物的结构和功能分析来测试。在特定目标3中,将病毒复制蛋白转染到哺乳动物细胞中将用于(i)确定细胞膜重组成双双层所需的最小病毒组分,以及(ii)表征稳定含聚合酶的寡聚体的蛋白质-蛋白质相互作用,因为这些界面代表病毒复制破坏和开发为潜在药物靶标的脆弱性位点。 公共卫生相关性:需要针对脊髓灰质炎病毒和类似病毒(如丙型肝炎和SARS)的新的抗病毒药物来治疗这些疾病的患者,并帮助防止将其用作针对未接种疫苗人群的生物武器的威胁。一种有希望的方法是靶向病毒复制新的自身所需的蛋白质。这项拟议中的研究将着眼于复制病毒基因所必需的蛋白质形成的组装体,并为未来的药物设计定位脆弱区域。

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 }}

ESTHER BULLITT其他文献

ESTHER BULLITT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('ESTHER BULLITT', 18)}}的其他基金

Exploiting the Salivary Arsenal to Inhibit Diarrheal Disease
利用唾液库抑制腹泻病
  • 批准号:
    10357830
  • 财政年份:
    2021
  • 资助金额:
    $ 36.01万
  • 项目类别:
Midwest Consortium for High Resolution Cryoelectron Microscopy
中西部高分辨率冷冻电子显微镜联盟
  • 批准号:
    10205086
  • 财政年份:
    2017
  • 资助金额:
    $ 36.01万
  • 项目类别:
CryoEM Data Collection Facility Consortium at NCM
NCM 的 CryoEM 数据收集设施联盟
  • 批准号:
    9975875
  • 财政年份:
    2017
  • 资助金额:
    $ 36.01万
  • 项目类别:
CryoEM Data Collection Facility Consortium at NCM
NCM 的 CryoEM 数据收集设施联盟
  • 批准号:
    9750738
  • 财政年份:
    2017
  • 资助金额:
    $ 36.01万
  • 项目类别:
Midwest Consortium for High Resolution Cryoelectron Microscopy
中西部高分辨率冷冻电子显微镜联盟
  • 批准号:
    9257031
  • 财政年份:
    2017
  • 资助金额:
    $ 36.01万
  • 项目类别:
CryoEM Data Collection Facility Consortium at NCMI
NCMI 的 CryoEM 数据收集设施联盟
  • 批准号:
    9000209
  • 财政年份:
    2016
  • 资助金额:
    $ 36.01万
  • 项目类别:
The Southeastern Consortium for Microscopy of MacroMolecular Machines
东南宏观分子机器显微镜联盟
  • 批准号:
    9317510
  • 财政年份:
    2016
  • 资助金额:
    $ 36.01万
  • 项目类别:
Towards the Disruption of Viral RNA Replication
致力于破坏病毒 RNA 复制
  • 批准号:
    8882459
  • 财政年份:
    2012
  • 资助金额:
    $ 36.01万
  • 项目类别:
Towards the Disruption of Viral RNA Replication
致力于破坏病毒 RNA 复制
  • 批准号:
    8500401
  • 财政年份:
    2012
  • 资助金额:
    $ 36.01万
  • 项目类别:
Towards the Disruption of Viral RNA Replication
致力于破坏病毒 RNA 复制
  • 批准号:
    8919492
  • 财政年份:
    2012
  • 资助金额:
    $ 36.01万
  • 项目类别:

相似海外基金

Development of a new generation of antiviral agents that are effective against drug-resistant viruses and prevent serious illness and sequelae.
开发新一代抗病毒药物,可有效对抗耐药病毒并预防严重疾病和后遗症。
  • 批准号:
    23K18186
  • 财政年份:
    2023
  • 资助金额:
    $ 36.01万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
A versatile structure-based therapeutic platform for development of VHH-based antitoxin and antiviral agents
一个多功能的基于结构的治疗平台,用于开发基于 VHH 的抗毒素和抗病毒药物
  • 批准号:
    10560883
  • 财政年份:
    2023
  • 资助金额:
    $ 36.01万
  • 项目类别:
Genetically encoded bicyclic peptide libraries for the discoveryof novel antiviral agents
用于发现新型抗病毒药物的基因编码双环肽库
  • 批准号:
    10730692
  • 财政年份:
    2021
  • 资助金额:
    $ 36.01万
  • 项目类别:
Design and synthesis of nucleosides to develop antiviral agents and oligonucleotide therapeutics
设计和合成核苷以开发抗病毒药物和寡核苷酸疗法
  • 批准号:
    21K06459
  • 财政年份:
    2021
  • 资助金额:
    $ 36.01万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Genetically encoded bicyclic peptide libraries for the discoveryof novel antiviral agents
用于发现新型抗病毒药物的基因编码双环肽库
  • 批准号:
    10189880
  • 财政年份:
    2021
  • 资助金额:
    $ 36.01万
  • 项目类别:
Computer-aided identification and synthesis of novel broad-spectrum antiviral agents
新型广谱抗病毒药物的计算机辅助鉴定和合成
  • 批准号:
    2404261
  • 财政年份:
    2020
  • 资助金额:
    $ 36.01万
  • 项目类别:
    Studentship
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
  • 批准号:
    10222540
  • 财政年份:
    2020
  • 资助金额:
    $ 36.01万
  • 项目类别:
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
  • 批准号:
    10669717
  • 财政年份:
    2020
  • 资助金额:
    $ 36.01万
  • 项目类别:
Association between sedentary lifestyle and liver cancer development in hepatitis C patients treated with direct-acting antiviral agents
接受直接抗病毒药物治疗的丙型肝炎患者久坐的生活方式与肝癌发展之间的关系
  • 批准号:
    20K10713
  • 财政年份:
    2020
  • 资助金额:
    $ 36.01万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
  • 批准号:
    10174522
  • 财政年份:
    2020
  • 资助金额:
    $ 36.01万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了