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Broad-spectrum antiviral GS-5734 to treat MERS-CoV and related emerging CoV

Broad-spectrum antiviral GS-5734 to treat MERS-CoV and related emerging CoV
广谱抗病毒药物 GS-5734 用于治疗 MERS-CoV 和相关的新出现的 CoV
批准号:
10189984
负责人:
Ralph S Baric
金额:
$45.81万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-05-08 至 2022-07-31
关键词:
AddressAnimal ModelAnimalsAntiviral AgentsAntiviral TherapyAttenuatedBiochemistryBirdsCamelsCell Culture TechniquesCell modelCellsChiropteraClinical TrialsCoronavirusCoronavirus InfectionsDataDevelopmentDiseaseDisease OutbreaksDrug KineticsEndotheliumEngineeringEpithelial CellsExonsFamilyFilovirusFluorescent in Situ HybridizationFosteringFutureGenerationsGeneticGenetic VariationGenomeGoalsHepatitisHumanImmuneIn VitroInfectionInnate Immune ResponseLicensureLungMammalsMeasurementMediatingMedicalMetabolicMetabolismMetagenomicsMiddle EastMiddle East Respiratory SyndromeMiddle East Respiratory Syndrome CoronavirusModelingMusMutateMutationNucleosidesParentsPathogenesisPathogenicityPathway interactionsPharmaceutical PreparationsPharmacodynamicsPharmacologic SubstancePredispositionPrimatesProdrugsProteinsPublic HealthRNARNA VirusesRNA chemical synthesisRNA replicationRNA-Directed RNA PolymeraseRecoveryResistanceResistance profileResolutionSARS coronavirusScienceSerumSevere Acute Respiratory SyndromeT-LymphocyteTestingTherapeuticToxic effectTransgenic MiceTreatment EfficacyViral GenomeViral PathogenesisVirusVirus ReplicationWild AnimalsZoonosesagedairway epitheliumalveolar type II cellanimal ecologyanti-viral efficacyantiviral immunitybiological systemsclinical applicationcoronavirus receptorcross-species transmissiondeep sequencingdesigndrug metabolismefficacy studyesterasefitnesshuman coronavirushuman diseasehuman modelimprovedin vivoin vivo evaluationin vivo imagingmetabolic abnormality assessmentmouse modelnonhuman primatenovel coronaviruspandemic diseasepathogenic viruspharmacokinetics and pharmacodynamicspre-clinicalpreclinical developmentprogramsrecombinant virusremdesivirreplicaseresistance mutationsingle moleculetranscriptome sequencingtripolyphosphateuptakeviral RNAviral fitnessvirology

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英文摘要
Project Summary Zoonotic viruses, like filoviruses and coronaviruses (CoV), represent a continuous and growing threat to global public health because they unpredictably emerge causing devastating outbreaks of pandemic disease. In the 21st century, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) emerged from zoonotic pools of viruses, causing severe disease in humans. MERS-CoV is endemic in camels in the Middle East with continuous new infections in humans. Although SARS-CoV is not currently a threat, several “prepandemic” SARS-like CoVs have been isolated from bats that replicate efficiently in human cells and are resistant to existing therapies. With the unpredictable overlap of human and wild animal ecologies, the potential for novel CoV emergence into humans is highly probable. Currently, there are no approved antiviral therapies for any human CoV infection. Broad-spectrum CoV therapies that control known human and zoonotic CoV infections would address an immediate unmet medical need and could counter future pandemic episodes. In partnership with Gilead Sciences, we have demonstrated that the nucleoside prodrug, GS-5734, is highly efficacious in inhibiting multiple human and zoonotic CoV in vitro and SARS-CoV in vivo. The primary goal of our program is to accelerate the preclinical development of GS-5734 and promote IND licensure for the MERS-CoV indication. To thoroughly evaluate the breadth of antiviral activity and predict efficacy against future emerging CoV, we will also assess efficacy against a panel of CoV representative of family-wide genetic diversity, including prepandemic zoonotic strains poised for emergence. Focusing on the highly pathogenic MERS-CoV, our unique partnership integrates: i) metagenomics and recombinant virus synthetic genome recovery, ii) primary human lung cell models, iii) cutting edge virology and biochemistry, iv) robust murine and primate models of human disease and v) state of the art metabolic and pharmacokinetic analysis. In Aim 1, we refine the pharmacokinetics, pharmacodynamics and breadth of GS-5734 through efficacy and metabolism studies in various primary human cells with a diverse array of human and zoonotic CoV and through the evaluation of in vivo efficacy in murine and non-human primate models of MERS- and SARS-CoV. In Aim 2, we select for resistance against SARS-CoV and MERS- CoV, and determine the effect of resistance on virus replication, fitness and susceptibility to treatment. In Aim 3, we determine if the mechanism of action of GS-5734 is a result of direct effects on viral RNA replication and/or alteration of antiviral immunity via deep sequencing and single molecule RNA fluorescence in situ hybridization of vehicle or drug treated infected cells and mice. We articulate a development strategy for broad- spectrum therapeutics that could be extended to a multitude of emerging viral pathogens threatening global public health.
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Core A: Administrative Core
Development of direct-acting flavivirus inhibitors
Core B: Virology Core
  • 批准号:
    10425027
  • 项目类别:
  • 资助金额:
    $215.31万
  • 财政年份:
    2022
  • 负责人:
    Ralph S Baric
  • 依托单位:
Research Project 1: Coronavirus antiviral lead development and combination testing
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