Journal
ACS INFECTIOUS DISEASES
Volume 5, Issue 10, Pages 1779-1793Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.9b00230
Keywords
antivirals; influenza A virus; oseltamivir; virus entry; antiviral drug resistance; kinases
Categories
Funding
- NIH [AI07647]
- [U19AI135972]
- [R56AI139015]
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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 beta (PIK3C2 beta) 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 PIK3C2 beta as a necessary host factor for influenza virus entry.
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