Isoflavone Agonists of IRF-3 Dependent Signaling Have Antiviral Activity Against RNA Viruses

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 2012 Apr 26

PMID 22532686

Citations 32

Authors

Kristin M Bedard

Myra L Wang

Sean C Proll

Yueh-Ming Loo

Michael G Katze

Michael Gale Jr

Shawn P Iadonato

Affiliations

Soon will be listed here.

Abstract

There is a growing need for novel antiviral therapies that are broad spectrum, effective, and not subject to resistance due to viral mutations. Using high-throughput screening methods, including computational docking studies and an interferon-stimulated gene 54 (ISG54)-luciferase reporter assay, we identified a class of isoflavone compounds that act as specific agonists of innate immune signaling pathways and cause activation of the interferon regulatory factor (IRF-3) transcription factor. The isoflavone compounds activated the ISG54 promoter, mediated nuclear translocation of IRF-3, and displayed highly potent activity against hepatitis C virus (HCV) and influenza virus. Additionally, these agonists efficiently activated IRF-3 in the presence of the HCV protease NS3-4A, which is known to blunt the host immune response. Furthermore, genomic studies showed that discrete innate immune pathways centered on IRF signaling were regulated following agonist treatment without causing global changes in host gene expression. Following treatment, the expression of only 64 cellular genes was significantly induced. This report provides the first evidence that innate immune pathways dependent on IRF-3 can be successfully targeted by small-molecule drugs for the development of novel broad-spectrum antiviral compounds.

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