Modelling how the altered usage of cell entry pathways by the SARS-CoV-2 Omicron variant may affect the efficacy and synergy of TMPRSS2 and Cathepsin B/L inhibitors

The SARS-CoV-2 Omicron variant harbours mutations in its spike protein, which may affect its cell entry, tropism, and response to interventions. To elucidate these effects, we developed a mathematical model of SARS-CoV-2 entry into cells and applied it to analyse recent in vitro data. SARS-CoV-2 enters cells using host proteases, either Cathepsin B/L or TMPRSS2. We estimated >4-fold increase and >3-fold decrease in entry efficiency using Cathepsin B/L and TMPRSS2, respectively, of the Omicron variant relative to the original or other strains in a cell type-dependent manner. Our model predicted that Cathepsin B/L inhibitors would be more and TMPRSS2 inhibitors less efficacious against the Omicron than the original strain. Furthermore, the two inhibitor classes would exhibit synergy, although the drug concentrations maximizing synergy would have to be tailored to the Omicron variant. These findings provide insights into the cell entry mechanisms of the Omicron variant and have implications for interventions.