title: High-throughput screening of a 100,000-compound library for inhibitors of influenza A virus (H3N2).
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-microM compound concentration against influenza strain A/Udorn/72 (H3N2). The "hit" rates (>50% inhibition of the viral cytopathic effect) from the 14- and 114-microM 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 (SI(50) = 10-49). Intriguingly, the screen at the higher concentration revealed several additional hits. Two of these hits were highly active with an SI(50) > 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Southern Research Institute, Birmingham, Alabama 35205, USA. severson@sri.org
authors.forename: William E
authors.initials: WE
authors.lastname: Severson
authors.forename: Michael
authors.initials: M
authors.lastname: McDowell
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ananthan
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Chung
authors.forename: Lynn
authors.initials: L
authors.lastname: Rasmussen
authors.forename: Melinda I
authors.initials: MI
authors.lastname: Sosa
authors.forename: E Lucile
authors.initials: EL
authors.lastname: White
authors.forename: James
authors.initials: J
authors.lastname: Noah
authors.forename: Colleen B
authors.initials: CB
authors.lastname: Jonsson
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001331:Automation; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D053122:Influenza A Virus, H3N2 Subtype / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D012254:Ribavirin / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin