title: Targeting Innate Immunity for Antiviral Therapy through Small Molecule Agonists of the RLR Pathway.
abstract: The cellular response to virus infection is initiated when pathogen recognition receptors (PRR) engage viral pathogen-associated molecular patterns (PAMPs). This process results in induction of downstream signaling pathways that activate the transcription factor interferon regulatory factor 3 (IRF3). IRF3 plays a critical role in antiviral immunity to drive the expression of innate immune response genes, including those encoding antiviral factors, type 1 interferon, and immune modulatory cytokines, that act in concert to restrict virus replication. Thus, small molecule agonists that can promote IRF3 activation and induce innate immune gene expression could serve as antivirals to induce tissue-wide innate immunity for effective control of virus infection. We identified small molecule compounds that activate IRF3 to differentially induce discrete subsets of antiviral genes. We tested a lead compound and derivatives for the ability to suppress infections caused by a broad range of RNA viruses. Compound administration significantly decreased the viral RNA load in cultured cells that were infected with viruses of the family Flaviviridae, including West Nile virus, dengue virus, and hepatitis C virus, as well as viruses of the families Filoviridae (Ebola virus), Orthomyxoviridae (influenza A virus), Arenaviridae (Lassa virus), and Paramyxoviridae (respiratory syncytial virus, Nipah virus) to suppress infectious virus production. Knockdown studies mapped this response to the RIG-I-like receptor pathway. This work identifies a novel class of host-directed immune modulatory molecules that activate IRF3 to promote host antiviral responses to broadly suppress infections caused by RNA viruses of distinct genera.
  
  
  OBJECTIVE
  Incidences of emerging and reemerging RNA viruses highlight a desperate need for broad-spectrum antiviral agents that can effectively control infections caused by viruses of distinct genera. We identified small molecule compounds that can selectively activate IRF3 for the purpose of identifying drug-like molecules that can be developed for the treatment of viral infections. Here, we report the discovery of a hydroxyquinoline family of small molecules that can activate IRF3 to promote cellular antiviral responses. These molecules can prophylactically or therapeutically control infection in cell culture by pathogenic RNA viruses, including West Nile virus, dengue virus, hepatitis C virus, influenza A virus, respiratory syncytial virus, Nipah virus, Lassa virus, and Ebola virus. Our study thus identifies a class of small molecules with a novel mechanism to enhance host immune responses for antiviral activity against a variety of RNA viruses that pose a significant health care burden and/or that are known to cause infections with high case fatality rates.
authors.affiliation: Department of Global Health, University of Washington, Seattle, Washington, USA.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Pattabhi
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA.
authors.forename: Courtney R
authors.initials: CR
authors.lastname: Wilkins
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Dong
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Knoll
authors.affiliation: Kineta, Inc., Seattle, Washington, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Posakony
authors.affiliation: Kineta, Inc., Seattle, Washington, USA.
authors.forename: Shari
authors.initials: S
authors.lastname: Kaiser
authors.affiliation: University of Texas Medical Branch at Galveston, Galveston National Laboratory, Galveston, Texas, USA.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Mire
authors.affiliation: Kineta, Inc., Seattle, Washington, USA.
authors.forename: Myra L
authors.initials: ML
authors.lastname: Wang
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA.
authors.forename: Renee C
authors.initials: RC
authors.lastname: Ireton
authors.affiliation: University of Texas Medical Branch at Galveston, Galveston National Laboratory, Galveston, Texas, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Geisbert
authors.affiliation: Kineta, Inc., Seattle, Washington, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Bedard
authors.affiliation: Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA Kineta, Inc., Seattle, Washington, USA.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Iadonato
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA looy@uw.edu mgale@uw.edu.
authors.forename: Yueh-Ming
authors.identifier: http://orcid.org/0000-0001-6294-7273
authors.initials: YM
authors.lastname: Loo
authors.affiliation: Department of Global Health, University of Washington, Seattle, Washington, USA Department of Immunology, University of Washington, Seattle, Washington, USA Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA looy@uw.edu mgale@uw.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007155:Immunologic Factors / Q000302:isolation & purification / Q000494:pharmacology*; D012328:RNA Viruses / Q000276:immunology* / Q000502:physiology*; D019562:Viral Load; D014776:Virus Cultivation; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D007155:Immunologic Factors