Lock out: targeting TMPRSS2 to block influenza and coronaviruses

Coronaviruses and influenza A viruses (IAV) can cause severe respiratory disease and have pandemic potential. Both viruses depend on priming of their glycoproteins by host cell proteases for the acquisition of infectivity, and the responsible enzymes represent potential targets for intervention. Initial studies suggested that these viruses may exploit redundant proteolytic systems. However, research conducted over the last two decades has pointed to a key role for a single enzyme in coronavirus and IAV priming, the transmembrane protease serine 2 (TMPRSS2). Interest in TMPRSS2 as a host dependency factor and therapeutic target intensified during the COVID-19 pandemic, prompting extensive investigation into its biology, substrate specificity, and pharmacological inhibition. Here, we review recent efforts to define the role of TMPRSS2 in coronavirus infection and to target this protease for antiviral intervention.