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

PLoS Computational Biology
Pranesh PadmanabhanNarendra Dixit

Abstract

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 est...Continue Reading

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Citations

Feb 20, 2021·ACS Chemical Neuroscience·Kartikay PrasadVijay Kumar
Feb 28, 2021·Journal of Medical Virology·Asim Z AbbasiNasir Jalal
Jul 6, 2021·Metabolism Open·Akeberegn Gorems AyeleZemene Demelash Kifle
Aug 4, 2021·Biochimica Et Biophysica Acta. General Subjects·Ali NajmeddinFarid Dorkoosh

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Clinical Trials Mentioned

NCT04321096
NCT04352400
NCT04338906

Software Mentioned

Engauge Digitizer
Mathematica
MATLAB

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