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 their in vivo efficacy. 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. These in vivo efficacy results further highlight the potential of RO-7 for development as antiviral therapy for influenza A and B virus infections.

Identification of the I38T PA Substitution as a Resistance Marker for Next-Generation Influenza Virus Endonuclease Inhibitors

“…We recently demonstrated that a novel PA inhibitor, RO-7, displays broad-spectrum anti-influenza activity in vitro ( 10 ) and protects mice from lethal challenge with both influenza A and B viruses ( 11 ). Although no resistant viruses were identified from the lungs of RO-7-treated, virus-infected mice, the potential for antiviral resistance to emerge with extended RO-7 pressure is unknown.…”

The antiviral effects of baloxavir marboxil against influenza A virus infection in ferrets

“…We previously reported the antiviral activities of BXA in vitro and in a mouse model. 9,[29][30][31] Interestingly, the half-life of BXA in ferrets was significantly shorter than in humans, Figure S4). Although high levels of BXM were detected in ferrets in contrast to humans and mice, its CEN inhibitory activity was ≥200-fold lower than that of BXA in in vitro studies, which indicates that the plasma concentration of BXA is more crucial for determining the dosing regimen of BXM.…”

Prevention and treatment of respiratory viral infections: Presentations on antivirals, traditional therapies and host-directed interventions at the 5th ISIRV Antiviral Group conference

“…The influenza virus acidic polymerase (PA) is a promising antiviral target because of its essential role in virus transcription. RO-7 is a new PA protein endonuclease inhibitor (Jones et al, 2017). RO-7 was tested against 36 influenza A and B viruses in MDCK and differentiated human bronchial epithelial cells.…”