High-Throughput Screening of a 100,000-Compound Library for Inhibitors of Influenza A Virus (H3N2)
Identifieur interne : 000391 ( Istex/Curation ); précédent : 000390; suivant : 000392High-Throughput Screening of a 100,000-Compound Library for Inhibitors of Influenza A Virus (H3N2)
Auteurs : William E. Severson ; Michael Mcdowell ; Subramaniam Ananthan [États-Unis] ; Dong-Hoon Chung ; Lynn Rasmussen ; Melinda I. Sosa ; E. Lucile White ; James Noah ; Colleen B. JonssonSource :
- Journal of Biomolecular Screening [ 1087-0571 ] ; 2008-10.
English descriptors
- Teeft :
- Antimicrob agents chemother, Antiviral, Antiviral activity, Approximate increase, Assay, Assay media, Biomol screen, Biomolecular, Biomolecular screening, Cell control, Cell control signal, Cell culture medium, Cell toxicity, Cell viability, Compound, Control compound, Cytopathic effect, Dmso, Dose response, Final concentration, Final dmso concentration, High humidity, Influenza, Influenza virus, Inhibitor, Inhibitory activities, Inhibitory effects, Madin darby, Mdck, Mdck cells, Molecular biology, Pandemic, Pandemic influenza, Plaque, Plaque assay, Plaque reduction assay, Plaque reduction assays, Plate reader, Postinfection, Primary screen, Ribavirin, Ribavirin triphosphate, Screening, Selective index, Serial dilutions, Severson, Standard deviation, Surface area, Test compound, Time points, Viral, Virus, Virus control signal, Virus life cycle.
Abstract
Using a highly reproducible and robust cell-based high-throughput screening (HTS) assay, the authors screened a 100,000-compound library at 14- and 114-µM compound concentration against influenza strain A/Udorn/72 (H3N2). The “hit” rates (>50% inhibition of the viral cytopathic effect) from the 14- and 114-µM screens were 0.022% and 0.38%, respectively. The hits were evaluated for their antiviral activity, cell toxicity, and selectivity in dose-response experiments. The screen at the lower concentration yielded 3 compounds, which displayed moderate activity (SI50 = 10-49). Intriguingly, the screen at the higher concentration revealed several additional hits. Two of these hits were highly active with an SI50 > 50. Time of addition experiments revealed 1 compound that inhibited early and 4 other compounds that inhibited late in the virus life cycle, suggesting they affect entry and replication, respectively. The active compounds represent several different classes of molecules such as carboxanilides, 1-benzoyl-3-arylthioureas, sulfonamides, and benzothiazinones, which have not been previously identified as having antiviral/anti-influenza activity. (Journal of Biomolecular Screening 2008:879-887)
Url:
DOI: 10.1177/1087057108323123
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William E. Severson<affiliation><mods:affiliation>E-mail: severson@sri.org</mods:affiliation>
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<affiliation><mods:affiliation>Department of Biochemistry and Molecular Biology</mods:affiliation>
<wicri:noCountry code="no comma">Department of Biochemistry and Molecular Biology</wicri:noCountry>
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<affiliation><mods:affiliation>Department of Biochemistry and Molecular Biology</mods:affiliation>
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<affiliation><mods:affiliation>Department of Biochemistry and Molecular Biology</mods:affiliation>
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<term>Assay media</term>
<term>Biomol screen</term>
<term>Biomolecular</term>
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<term>Dose response</term>
<term>Final concentration</term>
<term>Final dmso concentration</term>
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<term>Mdck</term>
<term>Mdck cells</term>
<term>Molecular biology</term>
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<term>Pandemic influenza</term>
<term>Plaque</term>
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<term>Plaque reduction assay</term>
<term>Plaque reduction assays</term>
<term>Plate reader</term>
<term>Postinfection</term>
<term>Primary screen</term>
<term>Ribavirin</term>
<term>Ribavirin triphosphate</term>
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<term>Serial dilutions</term>
<term>Severson</term>
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<front><div type="abstract" xml:lang="en">Using a highly reproducible and robust cell-based high-throughput screening (HTS) assay, the authors screened a 100,000-compound library at 14- and 114-µM compound concentration against influenza strain A/Udorn/72 (H3N2). The “hit” rates (>50% inhibition of the viral cytopathic effect) from the 14- and 114-µM screens were 0.022% and 0.38%, respectively. The hits were evaluated for their antiviral activity, cell toxicity, and selectivity in dose-response experiments. The screen at the lower concentration yielded 3 compounds, which displayed moderate activity (SI50 = 10-49). Intriguingly, the screen at the higher concentration revealed several additional hits. Two of these hits were highly active with an SI50 > 50. Time of addition experiments revealed 1 compound that inhibited early and 4 other compounds that inhibited late in the virus life cycle, suggesting they affect entry and replication, respectively. The active compounds represent several different classes of molecules such as carboxanilides, 1-benzoyl-3-arylthioureas, sulfonamides, and benzothiazinones, which have not been previously identified as having antiviral/anti-influenza activity. (Journal of Biomolecular Screening 2008:879-887)</div>
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