Development of MS2045 for inhibition of Zika methyltransferase

开发用于抑制寨卡病毒甲基转移酶的 MS2045

基本信息

项目摘要

Project Summary The Zika virus (ZIKV) is a member of the Flavivirus genus that includes other arthropod-borne human pathogens such as dengue virus and West Nile virus, among others. ZIKV’s link to microcephaly in newborn infants and the Guillan-Barré syndrome in adults has invigorated measures to develop a vaccine, as well as efforts to develop antivirals based on targeting enzymatic activities central to the life cycle and survival of ZIKV. One such enzymatic activity is encoded by the methyltransferase (MTase) domain, located at the N-terminus of the nonstructural protein NS5. Taking a structure informed approach, we have succeeded in identifying a novel “lead-like” compound (MS2045) for the inhibition of ZIKV’s NS5 MTase activity and for blocking its replication. MS2045 provides a basis for further chemistry and the development of even more potent inhibitors. In aim 1, we will a) design MS2045 analogs with the capacity to establish specific interactions with unique amino acids of ZIKV MTase as a means to provide additional selectivity against the human RNA 5’-cap MTases; b) chemically synthesize these analogs and produce them to a purity of 95% for in vitro and cell-based assays, and for structural studies. In aim 2, we will a) perform biophysical assays to assess the ability of these analogs to selectively bind the ZIKV NS5-MTase as compared to the human RNA 5’-cap MTases and test their ability to inhibit RNA methylation; b) test these analogs in viral cell-based assays to assess their efficacy in blocking viral replication; c) determine structures ZIKV NS5-Mtase with select analogs for additional, iterative rounds of structure activity relationships (SARs). Collectively, these studies will help to identify analogs of MS2045 that can be potentially developed into potent and selective inhibitors of NS5-MTase from ZIKV (and other pathogenic flaviviruses)
项目总结

项目成果

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科研奖励数量(0)
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ANEEL K. AGGARWAL其他文献

ANEEL K. AGGARWAL的其他文献

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{{ truncateString('ANEEL K. AGGARWAL', 18)}}的其他基金

Structure and Specificity of Restriction-Modification (R-M) Systems
限制性修饰(R-M)系统的结构和特异性
  • 批准号:
    10470890
  • 财政年份:
    2019
  • 资助金额:
    $ 25.35万
  • 项目类别:
Structure and Specificity of Restriction-Modification (R-M) Systems
限制性修饰(R-M)系统的结构和特异性
  • 批准号:
    10241952
  • 财政年份:
    2019
  • 资助金额:
    $ 25.35万
  • 项目类别:
Structure and Specificity of Restriction-Modification (R-M) Systems
限制性修饰(R-M)系统的结构和特异性
  • 批准号:
    10686907
  • 财政年份:
    2019
  • 资助金额:
    $ 25.35万
  • 项目类别:
Structure and Specificity of Restriction-Modification (R-M) Systems
限制性修饰(R-M)系统的结构和特异性
  • 批准号:
    10797690
  • 财政年份:
    2019
  • 资助金额:
    $ 25.35万
  • 项目类别:
Structure and Specificity of Restriction-Modification (R-M) Systems
限制性修饰(R-M)系统的结构和特异性
  • 批准号:
    10727038
  • 财政年份:
    2019
  • 资助金额:
    $ 25.35万
  • 项目类别:
Structure and Specificity of Restriction-Modification (R-M) Systems
限制性修饰(R-M)系统的结构和特异性
  • 批准号:
    10599570
  • 财政年份:
    2019
  • 资助金额:
    $ 25.35万
  • 项目类别:
Structure and mechanism of multisubunit complexes of DNA polymerase zeta
DNA聚合酶zeta多亚基复合物的结构和机制
  • 批准号:
    10249252
  • 财政年份:
    2018
  • 资助金额:
    $ 25.35万
  • 项目类别:
Structure and mechanism of multisubunit complexes of DNA polymerase zeta
DNA聚合酶zeta多亚基复合物的结构和机制
  • 批准号:
    10018049
  • 财政年份:
    2018
  • 资助金额:
    $ 25.35万
  • 项目类别:
Genome-wide detection of UV DNA damage by single molecule real time sequencing
通过单分子实时测序全基因组检测 UV DNA 损伤
  • 批准号:
    8807049
  • 财政年份:
    2014
  • 资助金额:
    $ 25.35万
  • 项目类别:
Structure-function analysis of a molecular switch for long-range diffusion on DNA
DNA 长程扩散分子开关的结构功能分析
  • 批准号:
    8927038
  • 财政年份:
    2014
  • 资助金额:
    $ 25.35万
  • 项目类别:

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腺嘌呤核苷酸转位酶在慢性阻塞性肺病(COPD)线粒体功能相关衰老中的作用
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使用 FRET 开发 miRNA 和腺嘌呤甲基转移酶的诺贝尔检测方法
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胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
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