2. Academic Validation
  3. Identifying enhancers of innate immune signaling as broad-spectrum antivirals active against emerging viruses

Identifying enhancers of innate immune signaling as broad-spectrum antivirals active against emerging viruses

  • Cell Chem Biol. 2022 Jul 21;29(7):1113-1125.e6. doi: 10.1016/j.chembiol.2022.05.009.
Ghizlane Maarifi 1,  Marie-France Martin 1,  Abderezak Zebboudj 1,  Aude Boulay 1,  Pierre Nouaux 1,  Juliette Fernandez 1,  Justine Lagisquet 1,  Dominique Garcin 2,  Raphael Gaudin 3,  Nathalie J Arhel 4,  Sébastien Nisole 5
Affiliations

Affiliations

  • 1 Viral Trafficking, Restriction and Innate Signaling, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS, 34090 Montpellier, France.
  • 2 Department of Microbiology and Molecular Medicine, University of Geneva School of Medicine, CMU, 1211 Geneva 4, Switzerland.
  • 3 Membrane Dynamics & Viruses, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS, 34090 Montpellier, France.
  • 4 Viral Trafficking, Restriction and Innate Signaling, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS, 34090 Montpellier, France. Electronic address: nathalie.arhel@irim.cnrs.fr.
  • 5 Viral Trafficking, Restriction and Innate Signaling, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS, 34090 Montpellier, France. Electronic address: sebastien.nisole@inserm.fr.
PMID: 35728599 DOI: 10.1016/j.chembiol.2022.05.009
Abstract

The increasingly frequent outbreaks of pathogenic viruses have underlined the urgent need to improve our arsenal of antivirals that can be deployed for future pandemics. Innate immunity is a powerful first line of defense against pathogens, and compounds that boost the innate response have high potential to act as broad-spectrum antivirals. Here, we harnessed localization-dependent protein-complementation assays (called Alpha Centauri) to measure the nuclear translocation of interferon regulatory factors (IRFs), thus providing a readout of innate immune activation following viral Infection that is applicable to high-throughput screening of immunomodulatory molecules. As proof of concept, we screened a library of kinase inhibitors on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Infection and identified Gilteritinib as a powerful enhancer of innate responses to viral Infection. This immunostimulatory activity of Gilteritinib was found to be dependent on the AXL-IRF7 axis and results in a broad and potent Antiviral activity against unrelated RNA viruses.

Keywords

SARS-CoV-2; broad-spectrum antivirals; drug screening; emerging viruses; innate immunity; interferon regulatory factors.

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