Padmanabhan, P and Dixit, NM (2023) Modelling how increased Cathepsin B/L and decreased TMPRSS2 usage for cell entry by the SARS-CoV-2 Omicron variant may affect the efficacy and synergy of TMPRSS2 and Cathepsin B/L inhibitors. In: Journal of Theoretical Biology, 572 .
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Abstract
The SARS-CoV-2 Omicron variant harbours many mutations in its spike protein compared to the original SARS-CoV-2 strain, which may alter its ability to enter cells, cell tropism, and response to interventions blocking virus entry. To elucidate these effects, we developed a mathematical model of SARS-CoV-2 entry into target cells and applied it to analyse recent in vitro data. SARS-CoV-2 can enter cells via two pathways, one using the host proteases Cathepsin B/L and the other using the host protease TMPRSS2. We found enhanced entry efficiency of the Omicron variant in cells where the original strain preferentially used Cathepsin B/L and reduced efficiency where it used TMPRSS2. The Omicron variant thus appears to have evolved to use the Cathepsin B/L pathway better but at the expense of its ability to use the TMPRSS2 pathway compared to the original strain. We estimated >4-fold enhanced efficiency of the Omicron variant in entry via the Cathepsin B/L pathway and >3-fold reduced efficiency via the TMPRSS2 pathway compared to the original or other strains in a cell type-dependent manner. Our model predicted that Cathepsin B/L inhibitors would be more efficacious and TMPRSS2 inhibitors less efficacious in blocking Omicron variant entry into cells than the original strain. Furthermore, model predictions suggested that drugs simultaneously targeting the two pathways would exhibit synergy. The maximum synergy and drug concentrations yielding it would differ for the Omicron variant compared to the original strain. Our findings provide insights into the cell entry mechanisms of the Omicron variant and have implications for intervention targeting these mechanisms.
| Item Type: | Journal Article |
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| Publication: | Journal of Theoretical Biology |
| Publisher: | Academic Press |
| Additional Information: | The copyright for this article belongs to the Author. |
| Keywords: | Cathepsin; COVID-19; Drug synergy; Mathematical modelling; Omicron; SARS-CoV-2; Spike protein; TMPRSS2; Viral kinetics |
| Department/Centre: | Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering Division of Mechanical Sciences > Chemical Engineering |
| Date Deposited: | 26 Jul 2023 06:24 |
| Last Modified: | 26 Jul 2023 06:24 |
| URI: | https://eprints.iisc.ac.in/id/eprint/82552 |
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