title: A Novel Endonuclease Inhibitor Exhibits Broad-Spectrum Anti-Influenza Virus Activity In Vitro.
abstract: Antiviral drugs are important in preventing and controlling influenza, particularly when vaccines are ineffective or unavailable. A single class of antiviral drugs, the neuraminidase inhibitors (NAIs), is recommended for treating influenza. The limited therapeutic options and the potential risk of antiviral resistance are driving the search for additional small-molecule inhibitors that act on influenza virus proteins. The acid polymerase (PA) of influenza viruses is a promising target for new antivirals because of its essential role in initiating virus transcription. Here, we characterized a novel compound, RO-7, identified as a putative PA endonuclease inhibitor. RO-7 was effective when added before the cessation of genome replication, reduced polymerase activity in cell-free systems, and decreased relative amounts of viral mRNA and genomic RNA during influenza virus infection. RO-7 specifically inhibited the ability of the PA endonuclease domain to cleave a nucleic acid substrate. RO-7 also inhibited influenza A viruses (seasonal and 2009 pandemic H1N1 and seasonal H3N2) and B viruses (Yamagata and Victoria lineages), zoonotic viruses (H5N1, H7N9, and H9N2), and NAI-resistant variants in plaque reduction, yield reduction, and cell viability assays in Madin-Darby canine kidney (MDCK) cells with nanomolar to submicromolar 50% effective concentrations (EC50s), low toxicity, and favorable selective indices. RO-7 also inhibited influenza virus replication in primary normal human bronchial epithelial cells. Overall, RO-7 exhibits broad-spectrum activity against influenza A and B viruses in multiple in vitro assays, supporting its further characterization and development as a potential antiviral agent for treating influenza.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Jones
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Bindumadhav M
authors.initials: BM
authors.lastname: Marathe
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Lerner
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kreis
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Gasser
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Philippe Noriel Q
authors.initials: PN
authors.lastname: Pascua
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Najera
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA elena.govorkova@stjude.org.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Govorkova
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000276:immunology; D004720:Endonucleases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D057809:HEK293 Cells; D006801:Humans; D007252:Influenza Vaccines / Q000276:immunology; D061985:Madin Darby Canine Kidney Cells; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000276:immunology; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D007252:Influenza Vaccines; D014764:Viral Proteins; D004720:Endonucleases