Project 4: Nuclease Inhibitors for Viruses of Pandemic Concern
项目 4:针对流行病病毒的核酸酶抑制剂
基本信息
- 批准号:10522813
- 负责人:
- 金额:$ 304.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-16 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoV5&apos-exoribonucleaseAddressAnimal ModelAntiviral AgentsAntiviral ResponseArenavirusBindingBiochemicalBiological AssayBolivian Hemorrhagic Fever VirusCOVID-19 screeningCell Culture TechniquesCell modelCellsChemicalsChemistryCollaborationsComplementComplexComputer ModelsCryoelectron MicroscopyDNADoseEffectivenessEnsureEnzymesExoribonucleasesFDA approvedFluorescenceGenerationsGenomeGoalsIn VitroInfectionInterferonsIonsJunin virusKineticsKnockout MiceLassa virusMetalsMidwestern United StatesMolecularMutagenesisNonstructural ProteinNucleoproteinsPathogenicityPharmaceutical ChemistryPharmaceutical PreparationsPharmacodynamicsPlayPropertyRNARNA chemical synthesisRNA replicationRNA-Directed RNA PolymeraseRepliconResistanceResolutionRibavirinRoleSARS-CoV-2 infectionSTAT1 geneStructureStructure-Activity RelationshipTechnologyTestingTransgenic MiceVaccinesValidationViralViral Hemorrhagic FeversViral PathogenesisVirusVirus DiseasesVirus InhibitorsVirus ReplicationWorkX-Ray Crystallographyanimal facilityaptamerbasedesigndrug candidateeffective therapyefficacy evaluationefficacy testinggain of functionhigh throughput screeningimprovedinhibitorlaboratory facilitymolecular dynamicsmouse modelnew therapeutic targetnovelnucleasenucleoside analogpandemic diseasepharmacokinetics and pharmacodynamicspreferenceremdesivirresistance mutationresponsestructural biologysynergismviral RNAvirtual screening
项目摘要
Project 4 – Nuclease Inhibitors for Viruses of Pandemic Concern
Abstract
SARS-CoV-2 (SARS2) and highly pathogenic arenaviruses including Lassa virus (LASV), Junin virus, and
Machupo virus share a structurally and functionally related 3'-to-5' exoribonuclease (ExoN) domain, which plays
essential roles in proofreading during RNA syntheses by the error-prone viral RNA-dependent RNA polymerase
(RdRp) and suppressing host antiviral responses. Project 4 is pursuing chemical inhibition of ExoN from these
viruses of pandemic concern, with the goal of blocking viral replication by lethal mutagenesis as well as mitigating
viral pathogenesis by reactivating host’s interferon responses. Our team has contributed extensively to the
structural and functional understanding of these viral ExoN enzymes, including the elucidation of their first atomic
structures and characterization of catalytic mechanisms. We have also developed robust fluorescence-based
assays to quantitatively analyze the ExoN catalytic activities, including a novel assay featuring fluorogenic RNA
aptamer substrates that enables a gain-of-function readout in ultra-high-throughput screening (uHTS).
Furthermore, we have used DNA-encoded chemistry technology (DEC-Tec) to obtain selective binders to
SARS2 ExoN and LASV nucleoprotein (NP) containing the ExoN domain. Building on these prior and preliminary
studies, we will continue to work closely with Core B and use 3 complementary approaches (uHTS, DEC-Tec,
and Virtual screening) to identify first-in-class viral ExoN inhibitors. We will then leverage the deep expertise of
Core C and Core D in medicinal chemistry and structural biology, respectively, to enhance the potency,
selectivity, and pharmacodynamic/kinetic properties of hit compounds for detailed antiviral studies in cell and
animal models by Core E. These studies will deliver antiviral drug candidates with a distinct mechanism of action
to complement those developed against established antiviral targets including RdRp, helping to address the
critical need for novel antiviral drugs against both SARS2 and the highly pathogenic arenaviruses that cause
fatal hemorrhagic fever infections.
项目4 -大流行病毒的核酸酶抑制剂
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Hideki Aihara其他文献
Hideki Aihara的其他文献
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{{ truncateString('Hideki Aihara', 18)}}的其他基金
Structural studies of viral replication and invasion
病毒复制和侵袭的结构研究
- 批准号:
10337889 - 财政年份:2016
- 资助金额:
$ 304.02万 - 项目类别:
Structural studies of viral replication and invasion
病毒复制和侵袭的结构研究
- 批准号:
10544179 - 财政年份:2016
- 资助金额:
$ 304.02万 - 项目类别:
Crystallographic studies of retroviral intasome complexes
逆转录病毒嵌体复合物的晶体学研究
- 批准号:
8919420 - 财政年份:2014
- 资助金额:
$ 304.02万 - 项目类别:
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