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. 2022 Jun 9;23(12):6468.
doi: 10.3390/ijms23126468.

A Study of Drug Repurposing to Identify SARS-CoV-2 Main Protease (3CLpro) Inhibitors

Seri Jo  1 , Luca Signorile  2 , Suwon Kim  1 , Mi-Sun Kim  1 , Oscar Huertas  2 , Raúl Insa  2 , Núria Reig  2 , Dong Hae Shin  1
Affiliations

A Study of Drug Repurposing to Identify SARS-CoV-2 Main Protease (3CLpro) Inhibitors

Seri Jo et al. Int J Mol Sci. .

Abstract

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wreaked havoc all over the world. Although vaccines for the disease have recently become available and started to be administered to the population in various countries, there is still a strong and urgent need for treatments to cure COVID-19. One of the safest and fastest strategies is represented by drug repurposing (DRPx). In this study, thirty compounds with known safety profiles were identified from a chemical library of Phase II-and-up compounds through a combination of SOM Biotech's Artificial Intelligence (AI) technology, SOMAIPRO, and in silico docking calculations with third-party software. The selected compounds were then tested in vitro for inhibitory activity against SARS-CoV-2 main protease (3CLpro or Mpro). Of the thirty compounds, three (cynarine, eravacycline, and prexasertib) displayed strong inhibitory activity against SARS-CoV-2 3CLpro. VeroE6 cells infected with SARS-CoV-2 were used to find the cell protection capability of each candidate. Among the three compounds, only eravacycline showed potential antiviral activities with no significant cytotoxicity. A further study is planned for pre-clinical trials.

Keywords: SARS-CoV-2 3CL protease; antiviral; drug repurposing; fret; inhibitory compounds.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Inhibition of SARS-CoV-2 3CLpro. Each data point represents the effect of each inhibitory compound against SARS-CoV-2 3CLpro compared with the control. The RFU are plotted against the log-concentration of inhibitory compounds. Each dot is expressed as the mean ± standard error of the mean (n = 3). RFU = relative fluorescence units.
Figure 2
Figure 2
Inhibition of three 3CL proteases. Each column represents the effect of each inhibitory compound against SARS-CoV-2 (left), SARS-CoV (middle), and MERS-CoV (right) 3CLpros compared with the control. All chemicals (20 μM) were confirmed for their inhibitory potential through a comparison of actual absorbance with the control at 490 nm. Data is expressed as the mean ± standard error of the mean (n = 3). RFU = relative fluorescence units.
Figure 3
Figure 3
Inhibition of SARS-CoV-2 infection in VeroE6 cells (a–f). The blue squares represent inhibition of SARS-CoV-2 infection (%), and the red triangles represent cell viability (%). Mean standard deviation (SD) was calculated from duplicate experiments.
Figure 4
Figure 4
A 2D schematic representation of the interactions between and schematic representations of cynarine (A), eravacycline (B), and prexasertib (C) docked on the catalytic cavity of SARS-CoV-2 3CLpro. The pink arrows represent hydrogen bonds, the blue dot line represents the covalent bond, and the green line represents a salt bridge. The electrostatic surface potential of SARS-CoV-2 3CLpro docked with compounds is depicted (red, negative; blue, positive; white, uncharged).
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