Targeting TMPRSS2 and Cathepsin B/L Together May Be Synergistic Against SARS-CoV-2 Infection

The entry of SARS-CoV-2 into target cells requires the activation of its surface spike protein, S, by host proteases. The host serine protease TMPRSS2 and cysteine proteases Cathepsin B/L can activate S, making two independent entry pathways accessible to SARS-CoV-2. Blocking the proteases prevents SARS-CoV-2 entry in vitro. This blockade may be achieved in vivo through ‘repurposing’ existing drugs and offers a potential treatment option for COVID-19, currently in clinical trials. Here, we found, surprisingly, that drugs targeting the two pathways, although independent, could display strong synergy in blocking virus entry. We predicted this synergy first using a mathematical model of SARS-CoV-2 entry and dynamics in vitro. The model considered the two pathways explicitly, let the entry efficiency through a pathway depend on the corresponding protease expression level, which varied across cells, and let inhibitors compromise the efficiency in a dose-dependent manner. We showed, analysing our model, that the synergy was novel and arose from effects of the drugs at both the single cell and the cell population levels. Validating our predictions, we found that available in vitro data on SARS-CoV-2 and SARS-CoV entry displayed this synergy. Exploiting the synergy may improve the deployability of drug combinations targeting host proteases required for SARS-CoV-2 entry.