Mechanisms of viral proteases in coronavirus replication and pathogenesis

病毒蛋白酶在冠状病毒复制和发病机制中的机制

基本信息

  • 批准号:
    8099729
  • 负责人:
  • 金额:
    $ 60.36万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-07-01 至 2015-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The long term goal of our research is to determine the role of viral protease and interferon antagonism activity in coronavirus replication and pathogenesis. Coronaviruses are positive strand RNA viruses which cause a range of illness, from relatively mild respiratory disease (croup and common cold like symptoms due to HCoV- NL63, 229e or OC43) to severe acute respiratory syndrome (SARS) outbreaks in humans. To date, there are no effective vaccines or antiviral drugs to limit the pathogenesis of any coronavirus infection. Clearly, we need to identify and understand the viral and host factors that contribute to efficient viral replication and pathogenesis to aid in the development of new therapeutics. Previously, we identified the papain-like protease (PLpro) of SARS-CoV as a critical determinant of viral replication and pathogenesis. During coronavirus replication, the input genomic RNA is translated to produce a replicase polyprotein which must be processed by viral papain-like and 3C-like proteases to generate the replication complex. We showed that PLpro processes the replicase polyprotein at three sites using a consensus recognition site of LXGG, similar to the consensus sequence recognized by de-ubiquitinating enzymes (DUBs). We solved the X-ray crystal structure of PLpro and demonstrated that it is indeed a DUB. However, the role of its viral DUB activity in pathogenesis remains to be determined. In addition, we found that PLpro exhibits interferon antagonism activity and that catalytic activity may not be required for full interferon antagonism. We hypothesize that distinct residues within the papain-like protease domain of coronaviruses are critical for mediating substrate specificity and interferon antagonism and that identification of these sites will provide novel targets for antiviral intervention. Here, we propose to investigate the biology of coronavirus papain-like proteases by comparing and contrasting the activity of papain-like proteases of SARS-CoV, HCoV-NL63, and murine coronavirus A59. Our specific aims are to: 1) Identify sites within the papain-like protease domains that are critical for polyprotein processing, deubiquitinating and deISGylating activity; 2) Determine residues within coronavirus papain-like proteases that are important for interferon antagonism and identify cellular proteins that interact with PLPs to block innate immunity; 3) Determine the domains, amino acids, and binding energies involved in protein-protein interactions between papain-like proteases and their binding partners; and 4) Determine if mutation of the PLpro or PLP2 domain alters evasion of ubiquitin- or ISG15-dependent innate immune responses. The results from this research will allow us to identify critical sites that mediate specificity of papain-like proteases and provide new insight into viral mechanisms for pathogenesis and evasion of the innate immune response. PUBLIC HEALTH RELEVANCE: The goal of our project is to determine how specific parts of a virus contribute to causing severe acute respiratory syndrome (SARS). We propose to use biochemical and molecular methods to study the SARS coronavirus protease and identify potential "Achilles' heels" of this protein. The results from our research will allow us to identify sites in the viral protease that may be targeted for antiviral drug development or modified to improve vaccine development.
描述(申请人提供):我们研究的长期目标是确定病毒蛋白酶和干扰素拮抗活性在冠状病毒复制和发病机制中的作用。冠状病毒是一种正链RNA病毒,可导致一系列疾病,从相对轻微的呼吸道疾病(由HCoV-NL63、229E或OC43引起的喉咙和普通感冒症状)到人类爆发的严重急性呼吸综合征(SARS)。到目前为止,还没有有效的疫苗或抗病毒药物来限制任何冠状病毒感染的发病机制。显然,我们需要识别和了解有助于病毒有效复制和致病的病毒和宿主因素,以帮助开发新的治疗方法。在此之前,我们发现SARS冠状病毒的木瓜蛋白酶(PLPro)是病毒复制和致病的关键决定因素。在冠状病毒复制过程中,输入的基因组RNA被翻译成复制酶多蛋白,该复制酶多蛋白必须被病毒类木瓜蛋白酶和类3C蛋白酶处理才能产生复制复合体。我们发现PLPro使用LXGG的共识识别位点在三个位点处理复制酶多蛋白,类似于去泛素化酶(DUBS)识别的共识序列。我们解决了PLPro的X射线晶体结构,证明了它确实是一种配音。然而,其病毒DUB活性在发病机制中的作用仍有待确定。此外,我们发现PLPro具有干扰素拮抗活性,并且完全干扰素拮抗可能不需要催化活性。我们假设冠状病毒类木瓜蛋白酶结构域中的不同残基对于介导底物特异性和干扰素拮抗至关重要,这些位点的识别将为抗病毒干预提供新的靶点。在这里,我们建议通过比较和对比SARS-CoV、HCoV-NL63和小鼠冠状病毒A59的木瓜蛋白样酶的活性来研究冠状病毒木瓜蛋白样蛋白酶的生物学特性。我们的具体目标是:1)确定木瓜蛋白样蛋白酶域中对多蛋白加工、去泛素化和去ISGyl化活性至关重要的位置;2)确定冠状病毒木瓜蛋白样蛋白酶中对干扰素拮抗重要的残基,并确定与PLP相互作用以阻断先天免疫的细胞蛋白;3)确定木瓜蛋白样蛋白酶及其结合伙伴之间的蛋白-蛋白质相互作用所涉及的结构域、氨基酸和结合能;以及4)确定PLPro或PLP2结构域的突变是否改变依赖泛素或ISG15的先天免疫反应。这项研究的结果将使我们能够确定关键的位置,中介木瓜蛋白酶样酶的特异性,并为病毒致病机制和逃避天然免疫反应提供新的见解。 公共卫生相关性:我们项目的目标是确定病毒的特定部分如何导致严重急性呼吸综合征(SARS)。我们建议使用生化和分子方法来研究SARS冠状病毒蛋白水解酶,并确定该蛋白潜在的“阿喀琉斯跟腱”。我们的研究结果将使我们能够确定病毒蛋白酶中可能被用于抗病毒药物开发或被修改以改进疫苗开发的位置。

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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Susan C. Baker其他文献

THE CONVERGENCE OF MULTIPLE MODELS OF MOTIVATION FOR SECOND LANGUAGE LEARNING : GARDNER
第二语言学习多种动机模式的融合:加德纳
  • DOI:
  • 发表时间:
    2005
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Maclntyre;Keith MacMaster;Susan C. Baker;Univasitl Colhge d Ca
  • 通讯作者:
    Univasitl Colhge d Ca
Overcome imposter syndrome: Contribute to working groups and build strong networks
克服冒名顶替综合症:为工作组做出贡献并建立强大的网络
  • DOI:
    10.1016/j.biocon.2024.110566
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    5.9
  • 作者:
    Amanda E. Bates;Megan A. Davies;Rick D. Stuart;Natali Lazzari;J. Lefcheck;Scott D. Ling;Camille Mellin;David Mouillot;Anthony T.F. Bernard;Scott Bennett;Christopher J. Brown;Michael T. Burrows;Claire L. Butler;J. Cinner;Ella Clausius;Antonia T. Cooper;Mark John Costello;Lara Denis;Graham J. Edgar;Yann Herrera Fuchs;Olivia J. Johnson;Cesc Gordó;Cyril Hautecoeur;Leah M. Harper;F. Heather;Tyson R. Jones;Anthony C. Markey;E. Oh;Matthew Rose;Paula A. Ruiz;José A. Sanabria;Jasmin M. Schuster;Joanna K. Schmid;Susan C. Baker
  • 通讯作者:
    Susan C. Baker
Timing and frequency are the critical factors affecting the impact of defoliation on long term growth of plantation eucalypts
  • DOI:
    10.1016/j.foreco.2017.02.004
  • 发表时间:
    2017-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Jane A. Elek;Susan C. Baker
  • 通讯作者:
    Susan C. Baker
Monoclonal Antibodies From Children With Acute Kawasaki Disease Identify a Common Antigenic Target in Fatal Cases Over 5 Decades
来自急性川崎病患儿的单克隆抗体在50多年的致死病例中识别出一个共同的抗原靶点
  • DOI:
    10.1016/j.labinv.2025.104131
  • 发表时间:
    2025-06-01
  • 期刊:
  • 影响因子:
    4.200
  • 作者:
    Anne H. Rowley;Robert Byrd;David Arrollo;Amornrat O’Brien;Stanford Shulman;Masaru Terai;Kwang-Youn Kim;Kassandra Mercado;Kristine Wylie;Robert Fialkowski;Susan C. Baker
  • 通讯作者:
    Susan C. Baker

Susan C. Baker的其他文献

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{{ truncateString('Susan C. Baker', 18)}}的其他基金

Investigating Interferon Antagonists in Delaying Innate Immune Responses to SARS-CoV-2
研究干扰素拮抗剂延迟对 SARS-CoV-2 的先天免疫反应
  • 批准号:
    10206579
  • 财政年份:
    2021
  • 资助金额:
    $ 60.36万
  • 项目类别:
Investigating Interferon Antagonists in Delaying Innate Immune Responses to SARS-CoV-2
研究干扰素拮抗剂延迟对 SARS-CoV-2 的先天免疫反应
  • 批准号:
    10449132
  • 财政年份:
    2021
  • 资助金额:
    $ 60.36万
  • 项目类别:
Investigating Interferon Antagonists in Delaying Innate Immune Responses to SARS-CoV-2
研究干扰素拮抗剂延迟对 SARS-CoV-2 的先天免疫反应
  • 批准号:
    10882676
  • 财政年份:
    2021
  • 资助金额:
    $ 60.36万
  • 项目类别:
Investigating Interferon Antagonists in Delaying Innate Immune Responses to SARS-CoV-2
研究干扰素拮抗剂延迟对 SARS-CoV-2 的先天免疫反应
  • 批准号:
    10657457
  • 财政年份:
    2021
  • 资助金额:
    $ 60.36万
  • 项目类别:
Mechanisms of viral proteases in coronavirus replication and pathogenesis
病毒蛋白酶在冠状病毒复制和发病机制中的机制
  • 批准号:
    7987943
  • 财政年份:
    2010
  • 资助金额:
    $ 60.36万
  • 项目类别:
Mechanisms of viral proteases in coronavirus replication and pathogenesis
病毒蛋白酶在冠状病毒复制和发病机制中的机制
  • 批准号:
    9096719
  • 财政年份:
    2010
  • 资助金额:
    $ 60.36万
  • 项目类别:
Mechanisms of viral proteases in coronavirus replication and pathogenesis
病毒蛋白酶在冠状病毒复制和发病机制中的机制
  • 批准号:
    8485522
  • 财政年份:
    2010
  • 资助金额:
    $ 60.36万
  • 项目类别:
Mechanisms of viral proteases in coronavirus replication and pathogenesis
病毒蛋白酶在冠状病毒复制和发病机制中的机制
  • 批准号:
    8686719
  • 财政年份:
    2010
  • 资助金额:
    $ 60.36万
  • 项目类别:
Mechanisms of viral proteases in coronavirus replication and pathogenesis
病毒蛋白酶在冠状病毒复制和发病机制中的机制
  • 批准号:
    8291352
  • 财政年份:
    2010
  • 资助金额:
    $ 60.36万
  • 项目类别:
Bronchial Epithelial Cultures and Kawasaki Disease
支气管上皮培养与川崎病
  • 批准号:
    7599596
  • 财政年份:
    2008
  • 资助金额:
    $ 60.36万
  • 项目类别:

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