High throughput screening for small molecule enhancers of the interferon signaling pathway to drive next-generation antiviral drug discovery.

PloS One
Dhara A PatelMichael J Holtzman

Abstract

Most of current strategies for antiviral therapeutics target the virus specifically and directly, but an alternative approach to drug discovery might be to enhance the immune response to a broad range of viruses. Based on clinical observation in humans and successful genetic strategies in experimental models, we reasoned that an improved interferon (IFN) signaling system might better protect against viral infection. Here we aimed to identify small molecular weight compounds that might mimic this beneficial effect and improve antiviral defense. Accordingly, we developed a cell-based high-throughput screening (HTS) assay to identify small molecules that enhance the IFN signaling pathway components. The assay is based on a phenotypic screen for increased IFN-stimulated response element (ISRE) activity in a fully automated and robust format (Z'>0.7). Application of this assay system to a library of 2240 compounds (including 2160 already approved or approvable drugs) led to the identification of 64 compounds with significant ISRE activity. From these, we chose the anthracycline antibiotic, idarubicin, for further validation and mechanism based on activity in the sub-µM range. We found that idarubicin action to increase ISRE activity...Continue Reading

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Citations

Sep 23, 2014·Nature Reviews. Immunology·Michael J HoltzmanXinyu Wang
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Methods Mentioned

BETA
PCR
transgenic
transfection

Software Mentioned

ProbeFinder
limma
Bioconductor
GraphPad Prism
cellHTS2
Lightcycler 480

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