In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication

Abstract

A novel coronavirus, named SARS-CoV-2, emerged in 2019 in China and rapidly spread worldwide. As no approved therapeutics exists to treat COVID-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass the time-consuming stages of drug development. In this study, we screened the PRESTWICK CHEMICAL LIBRARY composed of 1,520 approved drugs in an infected cell-based assay. The robustness of the screen was assessed by the identification of drugs that already demonstrated in vitro antiviral effect against SARS-CoV-2. Thereby, 90 compounds were identified as positive hits from the screen and were grouped according to their chemical composition and their known therapeutic effect. Then EC50 and CC50 were determined for a subset of 15 compounds from a panel of 23 selected drugs covering the different groups. Eleven compounds such as macrolides antibiotics, proton pump inhibitors, antiarrhythmic agents or CNS drugs emerged showing antiviral potency with 2 < EC50 ≤ 20 µM. By providing new information on molecules inhibiting SARS-CoV-2 replication in vitro, this study provides information for the selection of drugs to be further validated in vivo. Disclaimer: This study corresponds to the early stages of antiviral development and the results do not support by themselves the use of the selected drugs to treat SARS-CoV-2 infection.

Figure 1

Screening of 1,520 clinically approved compounds from PRESTWICK CHEMICAL LIBRARY and hits selection. The black dot line represents the threshold for positive hit compounds. Numbers associated with colors represent the plate numbers where the compounds are located.

Figure 2

Dose response curves of selected hit compounds. EC50: 50% inhibition, EC90: 90% inhibition. Compounds concentrations are presented in log scale for logarithmic interpolation. Dose response curves were generated using GraphPad Prism software version 7.0 (https://graphpad-prism.software.informer.com/7.0/).

Figure 3

Antiviral activity validation of the 17 compounds presented in Table 2 in Caco-2 cells at 5 and 10 µM. (A) Cytotoxicity of compounds in Caco-2 evaluated by the measure of cells viability. (B) Antiviral activity determined by the viral replication inhibition measurement in Caco-2. Graphical representations were generated using GraphPad Prism software version 7.0 (https://graphpad-prism.software.informer.com/7.0/).