Identifying enhancers of innate immune signaling as broad-spectrum antivirals active against emerging viruses. Issue 7 (21st July 2022)

• Record Type: Journal Article
• Authors: Maarifi, Ghizlane; Martin, Marie-France; Zebboudj, Abderezak; Boulay, Aude; Nouaux, Pierre; Fernandez, Juliette; Lagisquet, Justine; Garcin, Dominique; Gaudin, Raphael; Arhel, Nathalie J.; Nisole, Sébastien
• Is Part Of: Cell chemical biology. Volume 29:Issue 7(2022)
• Page Start: 1113
• Page End: 1125.e6
• Publication Date: 2022-07-21
• Subjects: innate immunity -- interferon regulatory factors -- drug screening -- SARS-CoV-2 -- emerging viruses -- broad-spectrum antivirals; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2022.05.009
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical abstract: Highlights: Compounds that boost the innate response can act as broad-spectrum antivirals Bioluminescence complementation is applied to measure nuclear translocation of IRFs Screening for enhancers of immune signaling by SARS-CoV-2 identified Gilteritinib Gilteritinib has broad antiviral activity that is dependent on the AXL-IRF7 axis Abstract : Compounds that enhance innate immunity can constitute potent broad-acting antivirals. Maarifi et al. identify immunostimulatory molecules applying bioluminescence complementation to measure innate immune activation. By assessing kinase inhibitors on SARS-CoV-2-infected cells, they identify Gilteritinib as an enhancer of innate responses with broad-acting antiviral activity.