High throughput screening of FDA-approved drug library reveals the compounds that promote IRF3-mediated pro-apoptotic pathway inhibit virus replication

Anna Glanz, Karan Chawla, Stephanie Fabry, Gayatri Subramanian, Julie Garcia, Bryanna Jay, Jacob Ciricillo, Ritu Chakravarti, R. Travis Taylor, Saurabh Chattopadhyay

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Interferon (IFN) regulatory factor 3 (IRF3) is the key transcription factor for the induction of IFN and antiviral genes. The absence of antiviral genes in IRF3 deficiency leads to susceptibility to a wide range of viral infections. Previously, we uncovered a function for nontranscriptional IRF3 (nt-IRF3), RLR (RIG-I-like receptor)-induced IRF3-mediated pathway of apoptosis (RIPA), which triggers apoptotic killing of virus-infected cells. Using knock-in mice expressing a transcriptionally inactive, but RIPA-active, IRF3 mutant, we demonstrated the relative contribution of RIPA to host antiviral defense. Given that RIPA is a cellular antiviral pathway, we hypothesized that small molecules that promote RIPA in virus-infected cells would act as antiviral agents. To test this, we conducted a high throughput screen of a library of FDA-approved drugs to identify novel RIPA activators. Our screen identified doxorubicin as a potent RIPA-activating agent. In support of our hypothesis, doxorubicin inhibited the replication of vesicular stomatitis virus, a model rhabdovirus, and its antiviral activity depended on its ability to activate IRF3 in RIPA. Surprisingly, doxorubicin inhibited the transcriptional activity of IRF3. The antiviral activity of doxorubicin was expanded to flavivirus and herpesvirus that also activate IRF3. Mechanistically, doxorubicin promoted RIPA by activating the extracellular signal-regulated kinase (ERK) signaling pathway. Finally, we validated these results using another RIPA-activating compound, pyrvinium pamoate, which showed a similar antiviral effect without affecting the transcriptional activity of IRF3. Therefore, we demonstrate that the RIPA branch of IRF3 can be targeted therapeutically to prevent virus infection.

Original languageEnglish
Article number442
JournalViruses
Volume12
Issue number4
DOIs
StatePublished - Apr 2020

Bibliographical note

Publisher Copyright:
© 2020 by the authors.

Keywords

  • Antiviral
  • Drug screen
  • Innate immunity
  • Interferon
  • IRF3
  • RIPA

ASJC Scopus subject areas

  • Infectious Diseases
  • Virology

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