Combination of MEK inhibitors and oseltamivir leads to synergistic antiviral effects after influenza A virus infection in vitro

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. (C) 2013 Elsevier B.V. All rights reserved.