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
- 批准号:10645958
- 负责人:
- 金额:$ 25.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-02 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVAdenineAdultAffinityAmericasAmino AcidsAntiviral AgentsAttenuatedBindingBinding SitesBiological AssayBiophysicsCellsChemistryCrystallizationDefectDengue VirusDevelopmentFlavivirusGoalsHIVHealthHepatitis CHumanIn VitroLeadLife Cycle StagesLinkMeasuresMethylationMethyltransferaseMicrocephalyMutationNewborn InfantNonstructural ProteinPathogenicityPathologyPatientsPharmaceutical ChemistryProcessRNARNA CapsRNA methylationStructureStructure-Activity RelationshipSyndromeTestingUgandaVaccinesVero CellsViralVirusVirus ReplicationWest Nile virusZIKAZIKV infectionZika Virusanalogantiviral drug developmentarthropod-bornebasechemical synthesiscofactordesignefficacy evaluationfuture outbreakhuman pathogeninhibitormembernovelpathogenscaffoldstructural biologyvaccine developmentviral RNAvirology
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)
项目摘要
寨卡病毒(ZIKV)是黄病毒属的成员,包括其他节肢动物传播的人类病原体
如登革热病毒和西尼罗河病毒等。ZIKV与新生儿小头畸形症的联系以及
成人的吉兰-巴雷综合征加强了开发疫苗的措施以及开发疫苗的努力
以ZIKV生命周期和生存中心的酶活性为靶点的抗病毒药物。这样的一个
酶活性由甲基转移酶(MTase)结构域编码,位于N端
非结构蛋白NS5。采取结构知情的方法,我们成功地确定了一部小说
“类铅”化合物(MS2045),用于抑制ZIKV的NS5 MTase活性并阻止其复制。
MS2045为进一步的化学和开发更有效的抑制剂提供了基础。在目标1中,
我们将a)设计MS2045类似物,具有与特定氨基酸建立特定相互作用的能力
ZIKV MTase作为提供对人RNA5‘-帽MTase的额外选择性的手段;b)化学
合成这些类似物并将它们生产到95%的纯度,用于体外和基于细胞的分析,以及用于
结构研究。在目标2中,我们将a)进行生物物理分析,以评估这些类似物的能力
与人RNA5‘-帽MTase相比,选择性结合ZIKV NS5-MTase,并检测其结合能力
抑制RNA甲基化;b)在基于病毒细胞的检测中测试这些类似物,以评估它们阻断病毒的有效性
复制;c)使用精选类似物确定结构ZIKV NS5-MTase,以进行额外的迭代循环
结构活性关系(SARS)。总的来说,这些研究将有助于识别MS2045的类似物
可以潜在地发展成为来自ZIKV(和其他致病病毒)的NS5-MTase的有效和选择性抑制剂
黄病毒)
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 }}
ANEEL K. AGGARWAL其他文献
ANEEL K. AGGARWAL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('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:
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:
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:
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:
相似海外基金
The Role of Adenine Nucleotide Translocase in Mitochondrial Dysfunction Associated Senescence in Chronic Obstructive Pulmonary Disease (COPD)
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
- 批准号:
10633608 - 财政年份:2023
- 资助金额:
$ 25.35万 - 项目类别:
Pathways of Succinate Accumulation and Adenine Nucleotide Depletion in Cardiac Ischemia
心脏缺血中琥珀酸积累和腺嘌呤核苷酸消耗的途径
- 批准号:
10534031 - 财政年份:2022
- 资助金额:
$ 25.35万 - 项目类别:
Pathways of Succinate Accumulation and Adenine Nucleotide Depletion in Cardiac Ischemia
心脏缺血中琥珀酸积累和腺嘌呤核苷酸消耗的途径
- 批准号:
10794933 - 财政年份:2022
- 资助金额:
$ 25.35万 - 项目类别:
Development of nobel assay methods for miRNA and adenine methyltransferase using FRET
使用 FRET 开发 miRNA 和腺嘌呤甲基转移酶的诺贝尔检测方法
- 批准号:
21K05120 - 财政年份:2021
- 资助金额:
$ 25.35万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Critical assessment of DNA adenine methylation in brain cells from healthy aging and Alzheimer's disease
健康老龄化和阿尔茨海默病脑细胞 DNA 腺嘌呤甲基化的批判性评估
- 批准号:
10365337 - 财政年份:2021
- 资助金额:
$ 25.35万 - 项目类别:
DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
- 批准号:
10033546 - 财政年份:2020
- 资助金额:
$ 25.35万 - 项目类别:
DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
- 批准号:
10613902 - 财政年份:2020
- 资助金额:
$ 25.35万 - 项目类别:
DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
- 批准号:
10226235 - 财政年份:2020
- 资助金额:
$ 25.35万 - 项目类别:
DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
- 批准号:
10396102 - 财政年份:2020
- 资助金额:
$ 25.35万 - 项目类别:
DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
- 批准号:
10705982 - 财政年份:2020
- 资助金额:
$ 25.35万 - 项目类别: