Inhibiting Viral Macrodomains Using Structure-Based Design

使用基于结构的设计抑制病毒宏域

基本信息

项目摘要

PROJECT 5: INHIBITING VIRAL MACRODOMAINS USING STRUCTURE-BASED DESIGN SUMMARY Viral macrodomains counter the host immune response by removing ADP-ribosylation modifications from host proteins, with important consequences for interferon and many other signaling pathways. Previous experiments in cell and animal models that use wild type and catalytically dead SARS-CoV and chikungunya virus (CHIKV) macrodomains validate these proteins as potential drug targets. However, no inhibitors exist for viral macrodomains. Using an integration of high throughput X-ray based fragment screen and docking, we have identified over 200 binders to the SARS-CoV-2 macrodomain (Mac1). Our subsequent assays guided the development of the first structurally characterized tool compounds that are more potent than the substrate ADP- ribose. In addition, we have leveraged the chemical knowledge to uncover additional scaffolds by docking. In this proposal, we advance compounds through a structure-based design approach, using biochemical assays against peptide binding and catalytic function. To identify starting points against the CHIKV macrodomain, we will perform a new X-ray crystallography-based fragment screen and perform an Ultra-large docking campaign (Screening Core). Our plan is to design compounds with low potency against human macrodomains and to leverage medicinal chemistry to drive potency against viral macrodomains. Our early activities will identify multiple alternative scaffolds with high potency in vitro to progress to target engagement in cells. Our cell-based aims will use cellular thermal shift and immunofluorescence of interferon treated cells as early markers of target engagement (Proteomics Core, In Vitro Virology Core). We will identify biomarkers by comparing RNAseq, proteomics, phosphoproteomics and ADP-Ribosylation AP-MS of compound treated cells to mutant macrodomains (both as a transgene and in the context of virus). During these activities, we will continue addressing aspects of permeability, off target effects, and other liabilities with the Medicinal Chemistry Core. We will progress to animal models compounds with cellular effects on replication with validated target engagement. Lead molecules with validated target engagement and minimal pharmacokinetic liabilities will allow us to test the effectiveness of candidate molecules in animal models of SARS-CoV-2 and CHIKV (In Vivo Virology Core). Based on previous studies in animal models with catalytically inactive macrodomain mutant viruses, we will prioritize molecules that drop viral load by at least 100-fold. Our work will generate a target package for further development by our industrial partner, Roche. The lessons of targeting SARS-CoV-2 and CHIKV macrodomains will be applicable to developing future agents against macrodomains in other viruses and those implicated in human disease.
项目5:使用基于结构的设计抑制病毒宏域 总结 病毒宏结构域通过从宿主中去除ADP-核糖基化修饰来对抗宿主免疫应答 蛋白质,对干扰素和许多其他信号通路具有重要影响。先前实验 在使用野生型和催化死亡的SARS-CoV和基孔肯雅病毒(CHIKV)的细胞和动物模型中, 大结构域验证了这些蛋白质作为潜在的药物靶标。然而,对于病毒, 宏域使用基于高通量X射线的片段筛选和对接的集成,我们 鉴定了超过200种SARS-CoV-2宏结构域(Mac 1)的结合物。我们随后的分析指导了 开发第一个结构上表征的工具化合物,其比底物ADP更有效, 核糖。此外,我们还利用化学知识通过对接发现了更多的支架。在 根据这一建议,我们通过基于结构的设计方法,使用生物化学分析, 对抗肽结合和催化功能。为了鉴定针对CHIKV宏结构域的起始点,我们 将进行一项新的基于X射线晶体学的碎片筛选,并进行超大型对接活动 (筛选核心)。我们的计划是设计对人类宏域具有低效力的化合物, 利用药物化学来驱动针对病毒宏域的效力。我们的早期活动将确定 在体外具有高效力的多种替代支架,以进展到细胞中的靶向接合。我们基于细胞的 aims将使用细胞热位移和干扰素处理细胞的免疫荧光作为靶点的早期标记物。 参与(蛋白质组学核心,体外病毒学核心)。我们将通过比较RNAseq, 化合物处理的细胞突变体的蛋白质组学、磷酸化蛋白质组学和ADP-核糖基化AP-MS 宏结构域(作为转基因和在病毒的情况下)。在这些活动中,我们将继续 解决渗透性、脱靶效应和药物化学核心的其他责任问题。 我们将进一步研究具有细胞复制效应的动物模型化合物,并验证其靶点 订婚具有经验证的靶点结合和最小药代动力学责任的先导分子将允许 我们在SARS-CoV-2和CHIKV动物模型中测试候选分子的有效性(体内 病毒学核心)。基于先前在具有催化失活的大结构域突变体的动物模型中的研究, 我们将优先考虑那些能将病毒载量降低至少100倍的分子。我们的工作将产生一个目标 我们的工业合作伙伴罗氏(Roche)提供了一个可供进一步开发的包装。针对SARS-CoV-2和 CHIKV宏结构域将适用于开发针对其他病毒中的宏结构域的未来试剂, 与人类疾病有关的基因

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 }}

James Solomon Fraser其他文献

James Solomon Fraser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('James Solomon Fraser', 18)}}的其他基金

Discovering and Manipulating Macromolecular Conformational Ensembles
发现和操纵大分子构象整体
  • 批准号:
    10710024
  • 财政年份:
    2022
  • 资助金额:
    $ 298.81万
  • 项目类别:
Equipment for Discovering and Manipulating Macromolecular Conformational Ensembles
发现和操纵大分子构象整体的设备
  • 批准号:
    10797971
  • 财政年份:
    2022
  • 资助金额:
    $ 298.81万
  • 项目类别:
Discovering and Manipulating Macromolecular Conformational Ensembles
发现和操纵大分子构象整体
  • 批准号:
    10406110
  • 财政年份:
    2022
  • 资助金额:
    $ 298.81万
  • 项目类别:
Model Comparison in Structural Biology
结构生物学模型比较
  • 批准号:
    8681145
  • 财政年份:
    2014
  • 资助金额:
    $ 298.81万
  • 项目类别:
Model Comparison in Structural Biology
结构生物学模型比较
  • 批准号:
    8828260
  • 财政年份:
    2014
  • 资助金额:
    $ 298.81万
  • 项目类别:
The Impact of Mutation on the Conformations and Recognition of Ubiquitin
突变对泛素构象和识别的影响
  • 批准号:
    8538838
  • 财政年份:
    2011
  • 资助金额:
    $ 298.81万
  • 项目类别:
The Impact of Mutation on the Conformations and Recognition of Ubiquitin
突变对泛素构象和识别的影响
  • 批准号:
    8335438
  • 财政年份:
    2011
  • 资助金额:
    $ 298.81万
  • 项目类别:
The Impact of Mutation on the Conformations and Recognition of Ubiquitin
突变对泛素构象和识别的影响
  • 批准号:
    8728042
  • 财政年份:
    2011
  • 资助金额:
    $ 298.81万
  • 项目类别:
The Impact of Mutation on the Conformations and Recognition of Ubiquitin
突变对泛素构象和识别的影响
  • 批准号:
    8213132
  • 财政年份:
    2011
  • 资助金额:
    $ 298.81万
  • 项目类别:

相似海外基金

Control of genomic integrity and virulence of Aspergillus fumigatus by ADP-ribosylation.
通过 ADP-核糖基化控制烟曲霉的基因组完整性和毒力。
  • 批准号:
    MR/X007472/1
  • 财政年份:
    2023
  • 资助金额:
    $ 298.81万
  • 项目类别:
    Fellowship
Understanding the impact of DNA ADP-ribosylation on telomere function in cancer cells
了解 DNA ADP-核糖基化对癌细胞端粒功能的影响
  • 批准号:
    10751121
  • 财政年份:
    2023
  • 资助金额:
    $ 298.81万
  • 项目类别:
Composition and function of telomeric multi-protein complexes and their regulation by ADP-ribosylation
端粒多蛋白复合物的组成和功能及其ADP-核糖基化的调节
  • 批准号:
    2748032
  • 财政年份:
    2022
  • 资助金额:
    $ 298.81万
  • 项目类别:
    Studentship
A Chemical Footprinting Approach towards Poly-ADP-Ribosylation-regulated Biomolecular Condensation
聚 ADP 核糖基化调节生物分子缩合的化学足迹方法
  • 批准号:
    10524783
  • 财政年份:
    2022
  • 资助金额:
    $ 298.81万
  • 项目类别:
Regulation of DNA repair by histone ADP-ribosylation
组蛋白 ADP 核糖基化调节 DNA 修复
  • 批准号:
    MR/W017350/1
  • 财政年份:
    2022
  • 资助金额:
    $ 298.81万
  • 项目类别:
    Research Grant
Regulation and function of site-specific protein poly-ADP-ribosylation
位点特异性蛋白质聚 ADP 核糖基化的调控和功能
  • 批准号:
    10668492
  • 财政年份:
    2022
  • 资助金额:
    $ 298.81万
  • 项目类别:
ADP-ribosylation of DNA in Mycobacterium tuberculosis
结核分枝杆菌 DNA 的 ADP-核糖基化
  • 批准号:
    BB/W016613/1
  • 财政年份:
    2022
  • 资助金额:
    $ 298.81万
  • 项目类别:
    Research Grant
A Chemical Footprinting Approach towards Poly-ADP-Ribosylation-regulated Biomolecular Condensation
聚 ADP 核糖基化调节生物分子缩合的化学足迹方法
  • 批准号:
    10610165
  • 财政年份:
    2022
  • 资助金额:
    $ 298.81万
  • 项目类别:
Role of Transcription Factor ADP-ribosylation in Breast Cancer Biology
转录因子 ADP-核糖基化在乳腺癌生物学中的作用
  • 批准号:
    10593900
  • 财政年份:
    2021
  • 资助金额:
    $ 298.81万
  • 项目类别:
A Chemical Footprinting Approach towards Poly-ADP-Ribosylation-regulated Biomolecular Condensation
聚 ADP 核糖基化调节生物分子缩合的化学足迹方法
  • 批准号:
    10389853
  • 财政年份:
    2021
  • 资助金额:
    $ 298.81万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了