High Throughput Screening of FDA-Approved Drug Library Reveals the Compounds that Promote IRF3-Mediated Pro-Apoptotic...

Area of Science:

• Virology
• Immunology
• Drug Discovery

Background:

• Interferon (IFN) regulatory factor 3 (IRF3) is crucial for antiviral gene induction.
• IRF3 deficiency increases susceptibility to viral infections.
• A nontranscriptional IRF3 function, RIPA, induces apoptosis in infected cells.

Purpose of the Study:

• To identify small molecules that activate the RIPA pathway as potential antiviral agents.
• To investigate the therapeutic potential of targeting the RIPA pathway.

Main Methods:

• High-throughput screening of FDA-approved drugs to find RIPA activators.
• Utilized knock-in mice expressing a RIPA-active IRF3 mutant.
• Tested antiviral activity against vesicular stomatitis virus, flavivirus, and herpesvirus.
• Investigated the role of ERK signaling pathway.

Main Results:

• Doxorubicin was identified as a potent RIPA activator.
• Doxorubicin inhibited viral replication by activating IRF3-mediated RIPA.
• Doxorubicin also inhibited IRF3 transcriptional activity.
• Pyrvinium pamoate validated RIPA activation as an antiviral mechanism.

Conclusions:

• The RIPA pathway of IRF3 represents a viable therapeutic target for antiviral treatments.
• Targeting nontranscriptional IRF3 functions offers a novel strategy against diverse viral infections.