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Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARSCoV- 2 infection

Padmanabhan, P and Desikan, R and Dixit, NM (2020) Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARSCoV- 2 infection. In: PLoS Computational Biology, 16 (12).

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Official URL: https://doi.org/10.1371/journal.pcbi.1008461


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' drugs, a potential treatment option for COVID-19 that is now 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. The synergy predicted was novel and arose from effects of the drugs at both the single cell and the cell population levels. Validating our predictions, available in vitro data on SARS-CoV-2 and SARS-CoV entry displayed this synergy. Further, analysing the data using our model, we estimated the relative usage of the two pathways and found it to vary widely across cell lines, suggesting that targeting both pathways in vivo may be important and synergistic given the broad tissue tropism of SARS-CoV-2. Our findings provide insights into SARS-CoV-2 entry into target cells and may help improve the deployability of drug combinations targeting host proteases required for the entry. © 2020 Padmanabhan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Item Type: Journal Article
Publication: PLoS Computational Biology
Publisher: Public Library of Science
Additional Information: The copyright for this article belongs to the Author(S).
Keywords: Amino acids; Cell culture; Cell proliferation; Drug dosage; Efficiency, Blockings; Cathepsin B; Clinical trial; Cysteine protease; In-vitro; In-vivo; Repurposing; Serine protease; Spike protein; Target cells, Coronavirus, aloxistatin; angiotensin converting enzyme 2; bafilomycin; camostat mesilate; cathepsin B; cathepsin B inhibitor; cathepsin L; transmembrane protease serine 2; cathepsin B; cathepsin L; coronavirus spike glycoprotein; CTSB protein, human; CTSL protein, human; protein binding; serine proteinase; spike protein, SARS-CoV-2; TMPRSS2 protein, human, animal cell; Article; cell level; cell population; controlled study; coronavirus disease 2019; drug targeting; enzyme activity; HeLa cell line; human; human cell; in vitro study; mathematical model; nonhuman; protein expression level; SARS coronavirus; Severe acute respiratory syndrome coronavirus 2; synergistic effect; Vero cell line; virus entry; animal; chemistry; Chlorocebus aethiops; drug effect; drug repositioning; drug therapy; genetics; physiology; theoretical model; virion, Animals; Cathepsin B; Cathepsin L; Chlorocebus aethiops; COVID-19; Drug Repositioning; Humans; Models, Theoretical; Protein Binding; SARS-CoV-2; Serine Endopeptidases; Spike Glycoprotein, Coronavirus; Vero Cells; Virion; Virus Internalization
Department/Centre: Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Division of Mechanical Sciences > Chemical Engineering
Date Deposited: 09 Jan 2023 09:40
Last Modified: 09 Jan 2023 09:40
URI: https://eprints.iisc.ac.in/id/eprint/78950

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