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

Pranesh Padmanabhan,Rajat Desikan,Narendra M Dixit,Miles P Davenport

doi:10.1371/journal.pcbi.1008461

Pranesh Padmanabhan, Rajat Desikan + Show 2 more

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

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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 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.

Highlights

As of August 13, 2020, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had infected a total of over 20 million people and caused over 744,000 deaths across the world, starting from the first reported infections in Wuhan, China in December, 2019 [1]
Our findings would help maximize the impact of combination therapies targeting host proteases involved in SARS-CoV-2 entry, which are currently in clinical trials
We considered in vitro experiments where a population of target cells is exposed in the presence or absence of protease inhibitors to virions expressing the SARS-CoV-2 spike protein, S, and the extent of infection is measured

Summary

Introduction

As of August 13, 2020, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had infected a total of over 20 million people and caused over 744,000 deaths across the world, starting from the first reported infections in Wuhan, China in December, 2019 [1]. The anti-malarial drug hydroxychloroquine, which has shown some activity against SARS-CoV-2 in vitro, has been approved in some countries as a prophylactic for high risk groups such as healthcare providers [13,14], recent studies have questioned its ability to prevent infection of lung cells [15,16]. Several such drugs are under clinical trials, including type I interferons and the HIV-1 drugs lopinavir and ritonavir [17]. Efforts are underway to develop effective vaccines [4,18]

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