An Influenza Virus Entry Inhibitor Targets Class II PI3 Kinase and Synergizes with Oseltamivir

Ryan O'Hanlon, Victor H. Leyva-Grado, Marion Sourisseau, Matthew J. Evans, Megan L. Shaw

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Two classes of antivirals targeting the viral neuraminidase (NA) and endonuclease are currently the only clinically useful drugs for the treatment of influenza. However, resistance to both antivirals has been observed in clinical isolates, and there was widespread resistance to oseltamivir (an NA inhibitor) among H1N1 viruses prior to 2009. This potential for resistance and lack of diversity for antiviral targets highlights the need for new influenza antivirals with a higher barrier to resistance. In this study, we identified an antiviral compound, M85, that targets host kinases, epidermal growth factor receptor (EGFR), and phosphoinositide 3 class II β (PIK3C2β) and is not susceptible to resistance by viral mutations. M85 blocks endocytosis of influenza viruses and inhibits a broad-spectrum of viruses with minimal cytotoxicity. In vitro, we found that combinations of M85 and oseltamivir have strong synergism. In the mouse model for influenza, treatment with the combination therapy was more protective against a lethal viral challenge than oseltamivir alone, indicating that development of M85 could lead to combination therapies for influenza. Finally, through this discovery of M85 and its antiviral mechanism, we present the first description of PIK3C2β as a necessary host factor for influenza virus entry.

Original languageEnglish
Pages (from-to)1779-1793
Number of pages15
JournalACS Infectious Diseases
Issue number10
StatePublished - 11 Oct 2019


  • antiviral drug resistance
  • antivirals
  • influenza A virus
  • kinases
  • oseltamivir
  • virus entry


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