Targeting cell signalling pathways to fight the flu: towards a paradigm change in anti-influenza therapy

Influenza is still one of the major plagues worldwide with the potential to cause pandemics. The increasing frequency of viral resistance to the four US Food and Drug Administration (FDA)-approved anti-influenza virus drugs underlines the urgent need for novel antivirals to be prepared for future influenza epidemics or pandemics. While the antivirals currently in use exclusively target viral factors, such as neuraminidase or the M2 ion channel, several pre-clinical approaches now focus on cellular factors or pathways that directly or indirectly interact with virus replication. Among these, inhibitors of intracellular signalling cascades that are essential for virus replication have been unravelled as the most promising candidates. This short article aims to highlight two of these novel approaches, namely, inhibition of the classical mitogenic Raf/MEK/ERK kinase cascade and blockade of the pathway that leads to activation of the transcription factor NF-kappaB. It has been shown that inhibition of both virus-induced pathways leads to impaired virus production in vitro and in vivo without side effects or the tendency to induce resistant virus variants. Besides the direct antiviral effect, such inhibitors may also exert additional beneficial effects by blocking the cytokine burst that contributes to the severity of infections by highly pathogenic influenza virus strains. Although these novel strategies are still in an early phase of pre-clinical development they might be very promising, especially with regard to prevention of viral resistance.