Abstract
SARS-CoV-2 is a novel coronavirus responsible for the COVID-19 pandemic, in which acute respiratory infections are associated with high socio-economic burden. We applied high-content screening to a well-defined collection of 5632 compounds including 3488 that have undergone previous clinical investigations across 600 indications. The compounds were screened by microscopy for their ability to inhibit SARS-CoV-2 cytopathicity in the human epithelial colorectal adenocarcinoma cell line, Caco-2. The primary screen identified 258 hits that inhibited cytopathicity by more than 75%, most of which were not previously known to be active against SARS-CoV-2 in vitro. These compounds were tested in an eight-point dose response screen using the same image-based cytopathicity readout. For the 67 most active molecules, cytotoxicity data were generated to confirm activity against SARS-CoV-2. We verified the ability of known inhibitors camostat, nafamostat, lopinavir, mefloquine, papaverine and cetylpyridinium to reduce the cytopathic effects of SARS-CoV-2, providing confidence in the validity of the assay. The high-content screening data are suitable for reanalysis across numerous drug classes and indications and may yield additional insights into SARS-CoV-2 mechanisms and potential therapeutic strategies.
Highlights
Background & SummaryCoronaviridae is a family of encapsulated single-stranded positive-sense RNA viruses that typically cause mild respiratory diseases such as the common cold in humans[1]
Three major outbreaks have occurred, the first caused by Severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002/20032, the second caused by Middle East respiratory syndrome coronavirus (MERS-CoV) in 20123, and the latest caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first recorded in December 2019 and was declared pandemic in March 20204
At the time of writing (9th December 2020), more than 69 million confirmed SARS-CoV-2 infections have been reported worldwide and more than 1.6 million people have died from the associated disease, COVID-195
Summary
Coronaviridae is a family of encapsulated single-stranded positive-sense RNA viruses that typically cause mild respiratory diseases such as the common cold in humans[1]. The search for effective drugs against SARS-CoV-2 could extend beyond known antivirals and anti-infectives if suitable high-throughput assays are used to identify candidates. One important avenue for reuse is to determine whether any of these clinical-stage compounds or related molecules could safely achieve active concentrations at the principal SARS-CoV-2 infection site, the human lung epithelium. In this manner, the combination of our in vitro activity data with information about tissue distribution may help to determine the most promising avenues for future COVID-19 preclinical and clinical studies
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