Discovery of SARS-CoV-2 antivirals using a replicon assay
Discovery of SARS-CoV-2 antivirals using a replicon assay
批准号:
10522048
负责人:
Stefan G Sarafianos
金额:
$65.76万
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
项目状态:
未结题
起止时间:
2022-08-01 至 2027-07-31
关键词:
2019-nCoVActive SitesAddressAffectAirAntiviral AgentsAntiviral TherapyBindingBiochemicalBiological AssayBiophysicsCOVID-19COVID-19 mortalityCaco-2 CellsCell LineCellsCessation of lifeCollectionCombined Modality TherapyCoronavirusDataDevelopmentDisclosureDiseaseDisease OutbreaksDrug KineticsDrug resistanceEffectivenessEnzyme KineticsFluorescence MicroscopyGenerationsGenesGenetic EngineeringGenomicsGrantHIV-1HIV-2Hepatitis B VirusHepatitis C virusHumanIn VitroIndividualInfluenzaInternationalKineticsLeadLegal patentLibrariesLiquid substanceMeasurementMeasuresMetalsMolecularMusMutationNonstructural ProteinPharmaceutical ChemistryPlasmidsPreparationProteinsPublic HealthPublished CommentPublishingRNARepliconReportingResistanceSARS coronavirusSARS-CoV-2 B.1.1.7SARS-CoV-2 B.1.351SARS-CoV-2 CAL.20CSARS-CoV-2 P.1SARS-CoV-2 antiviralSevere Acute Respiratory SyndromeSystemTechnologyTestingTimeUntranslated RegionsVaccinesVariantViralVirusVirus DiseasesVisualizationWashingtonWorkZIKAairway epitheliumanalogbasecell preparationcombatcytotoxicitydrug candidatedrug discoveryefficacy studyexperimental studyexpression cloningfitnesshelicasehigh throughput screeningimprovedin vivoinhibitorinnovationinventionlead optimizationminiaturizemonolayermouse modelnanomolarnovelpandemic diseaseremdesivirresistance mechanismresistance mutationscreeningsmall molecule inhibitorsmall molecule librariessocioeconomicsstable cell linesuccesssynergismtool
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) cause severe diseases in humans (COVID-
19) that presents a major threat for global public health. Since it was first reported in 12/2019, COVID-19 has
become a pandemic that continues to spread, with >246 million confirmed cases and >5 million deaths as of
11/02/2021. In addition to the human tragedy, the magnitude of the pandemic-driven implosion of global
economies is enormous. Although vaccines are now available, their efficacy appears to be reduced with
spreading viral strains. Remdesivir is the only approved antiviral targeting SARS-CoV-2, but it has little effect on
COVID-19 mortality. Therefore, it is critical to identify and develop additional antivirals to combat viral infection.
The following strong preliminary data enable targeting of SARS-CoV-2: 1) Construction of an extensive
collection of SARS-CoV-2 replicon systems that enable cutting-edge, rapid, and economical high-throughput
screening. 2) Preparation of cell lines that stably express SARS-CoV-2 replicon. 3) Preliminary screening of
chemical libraries led to the discovery of a novel SARS-CoV-2 antiviral, which has already been improved with
one round of optimization through medicinal chemistry efforts. 4) Multiplex visualization of single-genomic or
subgenomic (+) or (-) SARS-CoV-2 RNA and simultaneously viral and/or host proteins in individual infected cells.
5) Cutting-edge rapid high-throughput infectious virus BSL3 assays that enable kinetic, mechanistic, drug
resistance studies. 6) In-house cloning expression and purification of 10 SARS-CoV-2 non-structural proteins
(nsps). 7) Biochemical and biophysical assays to measure the enzymatic activities of several SARS-CoV and
SARS-CoV-2 nsp proteins and to measure compound binding to nsps.
We hypothesize that our recently developed replicon systems can be used for the discovery of anti-SARS-
CoV-2 hits, which upon hit-to-lead optimization can become COVID-19 drug candidates. To address this
hypothesis, we propose the following specific aims:
1. Use of SARS-CoV-2 replicon plasmid systems and SARS-CoV-2 replicon-expressing cell lines to screen
chemical libraries for antiviral hits.
2. Inhibition and resistance studies with prioritized inhibitors.
3. Hit-to-lead optimization
These studies will lead to antivirals with strong potency and pharmacokinetic profiles, setting the stage for
development of SARS-CoV-2 antivirals and combination therapies.
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Discovery of SARS-CoV-2 antivirals using a replicon assay
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批准号:10673119
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项目类别:
-
资助金额:$64.35万
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财政年份:2022
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负责人:Stefan G Sarafianos
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依托单位:
Behavior of HIV in Viral Environments (B-HIVE)
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批准号:10650864
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项目类别:
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资助金额:$675.93万
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财政年份:2022
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负责人:Stefan G Sarafianos
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依托单位:
Dynamics of HIV Core Interactions
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批准号:10650881
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项目类别:
-
资助金额:$117.14万
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财政年份:2022
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负责人:Stefan G Sarafianos
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依托单位:
Behavior of HIV in Viral Environments (B-HIVE)
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批准号:10508443
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项目类别:
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资助金额:$628.9万
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财政年份:2022
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负责人:Stefan G Sarafianos
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依托单位:
Dynamics of HIV Core Interactions
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批准号:10508450
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项目类别:
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资助金额:$122.86万
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财政年份:2022
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负责人:Stefan G Sarafianos
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依托单位:
Taking aim at HBV eradication using novel NRTIs and Capsid effectors
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批准号:9918244
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项目类别:
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资助金额:$56.87万
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财政年份:2017
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负责人:Stefan G Sarafianos
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依托单位:
Ultrapotent Inhibitors of Wild-type and Multi-drug Resistant HIV
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批准号:9605989
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项目类别:
-
资助金额:$27.04万
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财政年份:2017
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负责人:Stefan G Sarafianos
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依托单位:
Taking aim at HBV eradication using novel NRTIs and Capsid effectors
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批准号:9605893
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项目类别:
-
资助金额:$42.53万
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财政年份:2017
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负责人:Stefan G Sarafianos
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依托单位:
Reverse Transcriptase Multi-Class Drug Resistance and Rilpivirine Susceptibility in Diverse HIV-1 Subtypes
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批准号:9140626
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项目类别:
-
资助金额:$37.37万
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财政年份:2016
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负责人:Stefan G Sarafianos
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依托单位:
Development of HIV capsid-targeting antivirals that affect immune response by modulating capsid stability and have improved resistance profiles
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批准号:10437037
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项目类别:
-
资助金额:$53.81万
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财政年份:2016
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负责人:Stefan G Sarafianos
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依托单位:
Reverse Transcriptase Multi-Class Drug Resistance and Rilpivirine Susceptibility in Diverse HIV-1 Subtypes
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批准号:9353524
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项目类别:
-
资助金额:$12.41万
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财政年份:2016
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负责人:Stefan G Sarafianos
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依托单位:
Development of HIV capsid-targeting antivirals that affect immune response by modulating capsid stability and have improved resistance profiles
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批准号:10337556
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项目类别:
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资助金额:$55.14万
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财政年份:2016
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负责人:Stefan G Sarafianos
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依托单位:
Reverse Transcriptase Multi-Class Drug Resistance and Rilpivirine Susceptibility in Diverse HIV-1 Subtypes
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批准号:9280986
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项目类别:
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资助金额:$7.75万
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财政年份:2016
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负责人:Stefan G Sarafianos
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依托单位:
Development of HIV capsid-targeting antivirals that affect immune response by modulating capsid stability and have improved resistance profiles
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批准号:10620713
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项目类别:
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资助金额:$53.44万
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财政年份:2016
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负责人:Stefan G Sarafianos
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依托单位:
Structural studies of HIV Capsid with host factors and Capsid-targeting antivirals
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批准号:8993516
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项目类别:
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资助金额:$46.59万
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财政年份:2015
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负责人:Stefan G Sarafianos
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依托单位:
Structural studies of HIV Capsid with host factors and Capsid-targeting antivirals
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批准号:9285721
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项目类别:
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资助金额:$16.05万
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财政年份:2015
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负责人:Stefan G Sarafianos
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依托单位:
Structural studies of HIV Capsid with host factors and Capsid-targeting antivirals
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批准号:9089958
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项目类别:
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资助金额:$51.15万
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财政年份:2015
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负责人:Stefan G Sarafianos
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依托单位:
Capsid-Targeting Small Molecules Blocking HIV through Novel Mechanism of Action
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批准号:8802860
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项目类别:
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资助金额:$22.61万
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财政年份:2014
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负责人:Stefan G Sarafianos
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依托单位:
Capsid-Targeting Small Molecules Blocking HIV through Novel Mechanism of Action
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批准号:8731597
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项目类别:
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资助金额:$18.78万
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财政年份:2014
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负责人:Stefan G Sarafianos
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依托单位:
Novel antivirals targeting the RNase H activity of HIV reverse transcriptase
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批准号:9089807
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项目类别:
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资助金额:$74.94万
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财政年份:2012
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负责人:Stefan G Sarafianos
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依托单位:
海外基金