MEK inhibitors are very potent and promising compounds in
cancer therapy. Earlier investigations have demonstrated that they also possess
antiviral properties against influenza virus. This is due to the fact that activation of the Raf/
MEK/ERK signaling pathway is a prerequisite for influenza virus replication. As an alternative to vaccination,
antiviral therapy is a means to control
influenza. The appearance of influenza virus strains that are resistant to current treatment options demonstrates the need for new
antiviral strategies. The aim of the presented study was to investigate whether the combination of
MEK inhibitors with
oseltamivir, an inhibitor of viral
neuraminidase activity, would result in a synergistic
antiviral effect against pandemic
influenza A/Regensburg/D6/2009 (H1N1pdm09) virus. Here we show that four different
MEK inhibitors,
PD-0325901,
AZD-6244, AZD-8330 and
RDEA-119 that are orally available and at least in a phase I clinical trial against
cancer demonstrate
antiviral activity as single agents or in combination with
oseltamivir. Combination treatment increased the
antiviral activity of
oseltamivir significantly and resulted in a synergistic
antiviral effect as determined by the Chou-Talalay method. Taken together, the results demonstrate increased
antiviral activity of
oseltamivir after combination with
MEK inhibitors. These data are promising for further preclinical in vitro and in vivo investigations on the way to developing new
antiviral regimens against
influenza.