| Isoflavone agonists of IRF-3 dependent signaling have antiviral activity against RNA viruses. | |
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MedLine Citation:
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PMID: 22532686 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Kristin M Bedard; Myra L Wang; Sean C Proll; Yueh-Ming Loo; Michael G Katze; Michael Gale; Shawn P Iadonato |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-04-24 |
Journal Detail:
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Title: Journal of virology Volume: 86 ISSN: 1098-5514 ISO Abbreviation: J. Virol. Publication Date: 2012 Jul |
Date Detail:
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Created Date: 2012-06-08 Completed Date: 2012-08-15 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 0113724 Medline TA: J Virol Country: United States |
Other Details:
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Languages: eng Pagination: 7334-44 Citation Subset: IM |
Affiliation:
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Kineta, Inc., Seattle, Washington, USA. kbedard@kineta.us |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antiviral Agents
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metabolism* Hepacivirus / immunology*, physiology Humans Immunity, Innate Immunologic Factors / metabolism* Interferon Regulatory Factor-3 / biosynthesis* Isoflavones / agonists* Orthomyxoviridae / immunology*, physiology Protein Transport Signal Transduction / drug effects* Virus Replication |
| Grant Support | |
ID/Acronym/Agency:
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HSSN 272200900035C//PHS HHS; R43AI081335/AI/NIAID NIH HHS; R44 AI081335/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antiviral Agents; 0/IRF3 protein, human; 0/Immunologic Factors; 0/Interferon Regulatory Factor-3; 0/Isoflavones |
| Comments/Corrections | |
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