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 – 针对流行病病毒的核酸酶抑制剂
抽象的
SARS-CoV-2 (SARS2) 和高致病性沙粒病毒,包括拉沙病毒 (LASV)、胡宁病毒和
Machupo 病毒共享一个结构和功能相关的 3' 至 5' 核糖核酸外切酶 (ExoN) 结构域,该结构域发挥着
容易出错的病毒 RNA 依赖性 RNA 聚合酶在 RNA 合成过程中校对中的重要作用
(RdRp) 并抑制宿主抗病毒反应。项目 4 正在研究这些物质对 ExoN 的化学抑制
大流行病病毒,目的是通过致命诱变来阻止病毒复制并减轻
通过重新激活宿主的干扰素反应来控制病毒发病机制。我们的团队为该项目做出了巨大贡献
对这些病毒 ExoN 酶的结构和功能的理解,包括阐明它们的第一个原子
催化机制的结构和表征。我们还开发了强大的基于荧光的
定量分析 ExoN 催化活性的检测方法,包括一种以荧光 RNA 为特征的新型检测方法
适体底物可在超高通量筛选 (uHTS) 中实现功能增益读数。
此外,我们还使用DNA编码化学技术(DEC-Tec)来获得选择性结合剂
SARS2 ExoN 和 LASV 核蛋白 (NP) 含有 ExoN 结构域。建立在这些先前和初步的基础上
研究中,我们将继续与 Core B 密切合作,并使用 3 种互补方法(uHTS、DEC-Tec、
和虚拟筛选)来鉴定一流的病毒 ExoN 抑制剂。然后,我们将利用深厚的专业知识
核心C和核心D分别在药物化学和结构生物学中增强效力,
命中化合物的选择性和药效/动力学特性,用于细胞和病毒的详细抗病毒研究
Core E 的动物模型。这些研究将提供具有独特作用机制的抗病毒候选药物
补充针对包括 RdRp 在内的既定抗病毒目标而开发的药物,帮助解决
迫切需要针对 SARS2 和导致 SARS2 的高致病性沙粒病毒的新型抗病毒药物
致命的出血热感染。
项目成果
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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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