Antivirals

Alphaviruses feel the STING

PLoS Pathog. doi:10.1371/journal.ppat.1005324

Given the role of innate immune processes in inhibiting viral infection, pharmacologic activation of innate immunity represents an attractive antiviral strategy. Innate signaling cascades often culminate with the synthesis of type I interferons (IFNs) after initial recognition of microbe-associated molecules by pattern-recognition receptors (PRRs). To identify compounds that can stimulate IFN production as leads for new antivirals, Sali et al. performed a high-throughput screen for compounds that could activate a reporter under the control of an IFN- and IRF3-dependent promoter. IRF3 is a transcription factor required for PRR-mediated IFNβ transcription. The authors focused on one compound, G10, and found that it exhibits antiviral activity against the human pathogens Chikungunya and Venezuelan equine encephalitis viruses, two emerging mosquito-transmitted alphaviruses. Using a CRISPR-Cas9–mediated gene knockout approach, they found that G10's antiviral activity required IRF3 activation as well as STING, a PRR for cyclic dinucleotides. The authors could not observe direct binding of G10 to STING, and no target protein was immediately identified; instead, the authors hypothesize that another upstream PRR acts as the efficacy target of G10. These results suggest that pharmacologic targeting of STING-dependent, IRF3-terminal signaling pathways represents a potentially viable antiviral strategy.

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Bucci, M. Alphaviruses feel the STING. Nat Chem Biol 12, 53 (2016). https://doi.org/10.1038/nchembio.2012

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