New approaches to influenza therapy

Influenza and other respiratory diseases are a major cause of global morbidity and mortality. The high mutation rate of influenza viruses renders current vaccines ineffective after a single influenza season and vaccines effective against seasonal influenza do not protect against pandemic influenza. Therefore, antiviral treatment is of central importance to combat influenza. However, currently available antivirals target virus encoded proteins, the ion channel M2 and the neuraminidase, which can change rapidly in the presence of drug, rendering viruses resistant to therapy. As a consequence, new therapeutic approaches must be established and invariable host cell factors, which are required for viral spread but dispensable for cellular survival, are interesting candidates. The activity of host cell proteases which cleave and activate the influenza virus hemagglutinin (HA) is essential for viral infectivity and the responsible proteins are potential targets for antiviral intervention. Recently, several type II transmembrane serine proteases (TTSP) were shown to activate influenza viruses in cell culture and a single TTSP, TMPRSS2, was found to be essential for influenza virus activation in the host. In the present review, we will first provide a brief overview of potential cellular targets for novel anti-influenza therapies. Then we will discuss in detail the influenza virus activation by TTSPs and the therapeutic potential of compounds which block this process.