Inhibiting Viral Macrodomains Using Structure-Based Design
Inhibiting Viral Macrodomains Using Structure-Based Design
批准号:
10512631
负责人:
James Solomon Fraser
金额:
$298.81万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-05-16 至 2025-04-30
关键词:
2019-nCoVADP ribosylationAddressAdenosine Diphosphate RiboseAnimal ModelAnimalsBindingBiochemicalBiochemistryBiological AssayBiological MarkersCOVID-19 treatmentCatalogsCatalysisCell LineCell modelCellsChemicalsChemistryChikungunya virusCommunicable DiseasesComputational BiologyComputer AnalysisCrystallographyDefectDevelopmentDockingDropsDrug DesignDrug KineticsDrug TargetingElementsFeedbackFoundationsFutureHeadHumanImmune responseImmunofluorescence ImmunologicImmunologicsIn VitroIndustrializationInfectionInterferonsKnowledgeLeadLettersMeasuresModelingModificationMonitorMusPeptidesPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPost-Translational Protein ProcessingPropertyProteinsProteomicsReportingRoentgen RaysSARS coronavirusSideSignal PathwaySignal TransductionSpecificityStructureTestingToxicologyTransgenesViralViral Load resultVirusVirus DiseasesWorkX-Ray Crystallographyanalogbasecellular targetingcomputational chemistrydesigneffectiveness testingexperimental studyhuman diseasein vivoinhibitormutantpandemic diseasephosphoproteomicsprogramsresponsescaffoldscreeningside effectstructural biologytargeted biomarkertherapeutic evaluationtooltranscriptome sequencingvirology
中文摘要
项目5:利用基于结构的设计抑制病毒大结构域
英文摘要
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.
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专著(0)
科研奖励(0)
会议论文
Discovering and Manipulating Macromolecular Conformational Ensembles
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批准号:10710024
-
项目类别:
-
资助金额:$59.76万
-
财政年份:2022
-
负责人:James Solomon Fraser
-
依托单位:
Equipment for Discovering and Manipulating Macromolecular Conformational Ensembles
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批准号:10797971
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项目类别:
-
资助金额:$6.32万
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财政年份:2022
-
负责人:James Solomon Fraser
-
依托单位:
Discovering and Manipulating Macromolecular Conformational Ensembles
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批准号:10406110
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项目类别:
-
资助金额:$46.03万
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财政年份:2022
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负责人:James Solomon Fraser
-
依托单位:
Model Comparison in Structural Biology
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批准号:8681145
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项目类别:
-
资助金额:$19.09万
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财政年份:2014
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负责人:James Solomon Fraser
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依托单位:
Model Comparison in Structural Biology
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批准号:8828260
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项目类别:
-
资助金额:$22.8万
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财政年份:2014
-
负责人:James Solomon Fraser
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依托单位:
The Impact of Mutation on the Conformations and Recognition of Ubiquitin
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批准号:8538838
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项目类别:
-
资助金额:$37.47万
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财政年份:2011
-
负责人:James Solomon Fraser
-
依托单位:
The Impact of Mutation on the Conformations and Recognition of Ubiquitin
-
批准号:8335438
-
项目类别:
-
资助金额:$35.63万
-
财政年份:2011
-
负责人:James Solomon Fraser
-
依托单位:
The Impact of Mutation on the Conformations and Recognition of Ubiquitin
-
批准号:8728042
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项目类别:
-
资助金额:$38.63万
-
财政年份:2011
-
负责人:James Solomon Fraser
-
依托单位:
The Impact of Mutation on the Conformations and Recognition of Ubiquitin
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批准号:8213132
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项目类别:
-
资助金额:$33.18万
-
财政年份:2011
-
负责人:James Solomon Fraser
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依托单位:
海外基金