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High-Throughput Screening of a 100,000-Compound Library for Inhibitors of Influenza A Virus (H3N2)

Department of Biochemistry and Molecular Biology, severson{at}sri.org

Michael McDowell

Department of Biochemistry and Molecular Biology

Subramaniam Ananthan

Department of Chemistry, Southern Research Institute, Birmingham, Alabama

Dong-Hoon Chung

Department of Biochemistry and Molecular Biology

Lynn Rasmussen

High-Throughput Screening Center

Melinda I. Sosa

High-Throughput Screening Center

E. Lucile White

High-Throughput Screening Center

James Noah

Department of Biochemistry and Molecular Biology

Colleen B. Jonsson

Department of Biochemistry and Molecular Biology

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)

Key Words: influenza • HTS • high-throughput screening • antivirals

This version was published on October 1, 2008

Journal of Biomolecular Screening, Vol. 13, No. 9, 879-887 (2008)
DOI: 10.1177/1087057108323123


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