title: The PA Endonuclease Inhibitor RO-7 Protects Mice from Lethal Challenge with Influenza A or B Viruses.
abstract: Current influenza treatment relies on a single class of antiviral drugs, the neuraminidase inhibitors (NAIs), raising concern over the potential emergence of resistant variants and necessitating the development of novel drugs. In recent years, investigational inhibitors targeting the endonuclease activity of the influenza acidic polymerase (PA) protein have yielded encouraging results, although there are only limited data on theirin vivoefficacy. Here, we examined the antiviral potential of the PA endonuclease inhibitor RO-7 in prophylactic and therapeutic regimens in BALB/c mice inoculated with influenza A/California/04/2009 (H1N1)pdm09 or B/Brisbane/60/2008 viruses, which represent currently circulating antigenic variants. RO-7 was administered to mice intraperitoneally twice daily at dosages of 6, 15, or 30 mg/kg/day for 5 days, starting 4 h before or 24 or 48 h after virus inoculation, and showed no adverse effects. Prophylactic administration completely protected mice from lethal infection by influenza A or B virus. The level of therapeutic protection conferred depended upon the time of treatment initiation and RO-7 dosage, resulting in 60 to 100% and 80 to 100% survival with influenza A and B viruses, respectively. RO-7 treatment significantly decreased virus titers in the lung and lessened the extent and severity of lung damage. No PA endonuclease-inhibitor resistance was observed in viruses isolated from lungs of RO-7-treated mice, and the viruses remained susceptible to the drug at nanomolar concentrations in phenotypic assays. Thesein vivoefficacy results further highlight the potential of RO-7 for development as antiviral therapy for influenza A and B virus infections.
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: Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Gasser
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; D019072:Antibiotic Prophylaxis; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D004720:Endonucleases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009980:Influenza A virus / Q000187:drug effects*; D009981:Influenza B virus / Q000187:drug effects*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D056990:Post-Exposure Prophylaxis; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C066022:ring-opened 7-(2-hydroxyethyl)guanine; D006147:Guanine; D004720:Endonucleases
keywords: PA endonuclease; PA polymerase; antiviral; antiviral agents; influenza A virus; influenza B virus; mouse model