A SARS-CoV-2 cytopathicity dataset generated by high-content screening of a large drug repurposing collection

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.

Comparison of anti-SARS-CoV-2 activity and intracellular metabolism of remdesivir and its parent nucleoside

“…3 ). Anti-SARS-CoV-2 activity of remdesivir in Caco-2 cells is usually measured by analyzing cytopathic effect (EC 50 ranging from 0.1 to 0.8 μM ( Meyer et al, 2020 ; Ellinger et al, 2021 ; Bojkova et al, 2020 )) or by assessing virus expression using RT-qPCR (EC 50 = 46 nM) ( Krüger et al, 2021 ). In our hands, we observed a correlation between the higher potency of remdesivir vs GS-441524 (EC 50 of 1 nM vs 80 nM, respectively, or 0.018 μM vs 1.3 μM by icSARS-CoV-2-mNG inhibition assay) in Caco-2 cells and the high levels of active NTP (308 vs 4.6 pmol/million cells, respectively) formed in this cell line.…”

A machine learning platform to estimate anti-SARS-CoV-2 activities

“…To confirm the utility of our models, we collected three additional datasets from the literature and submitted these molecules (external to our training/validation/test sets) as input for prediction. First, we used a database for COVID-19 experiments 27 to explore and download recently published [28][29][30][31][32][33][34][35][36][37] in vitro COVID-19 bioactivity data of the reported compounds. After removing compounds already included in the NCATS experiments, we identified 27 external compounds active in anti-SARS-CoV-2 CPE assays (see Supplementary Table 4).…”

“…59), with eight compounds predicted as inactive. Among those predicted to be inactive, the majority stem from the work by Ellinger and colleagues 37 , which were derived from Caco-2 cells for CPE experiments. There is a high degree of variability between these two CPE assays (Caco-2 versus Vero E6), which explains the lack of predictivity using Vero E6-trained CPE models for Caco-2 data.…”

Could Histamine H1 Receptor Antagonists Be Used for Treating COVID-19?

“…Loratadine is a H1 receptor antagonist prescribed for the treatment of hay fever and other allergic diseases. Recently, loratadine was reported to inhibit SARS-CoV-2 with an IC50 of 15.13 µM in Caco-2 cells [ 75 ]. Desloratadine could prevent SARS-CoV-2 pseudotyped virus entry in ACE2-overexpressing HEK293T cells, and the antiviral effect of desloratadine was stronger compared to loratadine [ 76 ].…”