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. 2021 Apr 3;9(4):756.
doi: 10.3390/microorganisms9040756.

A Study of 3CLpros as Promising Targets against SARS-CoV and SARS-CoV-2

Seri Jo  1 , Suwon Kim  1 , Jahyun Yoo  1 , Mi-Sun Kim  1 , Dong Hae Shin  1
Affiliations

A Study of 3CLpros as Promising Targets against SARS-CoV and SARS-CoV-2

Seri Jo et al. Microorganisms. .

Abstract

The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), results in serious chaos all over the world. In addition to the available vaccines, the development of treatments to cure COVID-19 should be done quickly. One of the fastest strategies is to use a drug-repurposing approach. To provide COVID-19 patients with useful information about medicines currently being used in clinical trials, twenty-four compounds, including antiviral agents, were selected and assayed. These compounds were applied to verify the inhibitory activity for the protein function of 3CLpros (main proteases) of SARS-CoV and SARS-CoV-2. Among them, viral reverse-transcriptase inhibitors abacavir and tenofovir revealed a good inhibitory effect on both 3CLpros. Intriguingly, sildenafil, a cGMP-specific phosphodiesterase type 5 inhibitor also showed significant inhibitory function against them. The in silico docking study suggests that the active-site residues located in the S1 and S2 sites play key roles in the interactions with the inhibitors. The result indicates that 3CLpros are promising targets to cope with SAR-CoV-2 and its variants. The information can be helpful to design treatments to cure patients with COVID-19.

Keywords: FRET; SARS-CoV-2 3CL protease; antiviral; drug repurposing; 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
Inhibitory screening data of the chemical library against SARS-CoV and SARS-CoV-2 3CLpros. All chemical (40 μM) were confirmed for their inhibitory potential through a comparison of actual absorbance with control at 490 nm. Three chemicals (Nos. 2-1, 3-1 and 5-4) were not plotted, due to the abnormal surge of Relative Fluorescence Units (RFU) after the proteolytic cleavage of the substrate. 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).
Figure 2
Figure 2
Results from the FRET method. Each data point represents the effect of each inhibitory compound against (A) SARS-CoV 3CLpro and (B) SARS-CoV-2 3CLpro, compared to 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 3
Figure 3
Predicted docking modes of each inhibitory compound in the catalytic site of SARS-CoV CLpro and SARS-CoV-2 CLpro. Docking poses of (a,d) abacavir, (b,e) tenofovir and (c,f) sildenafil were overlapped and depicted on the semi-transparent electrostatic surface potentials (red, negative; blue, positive; white, uncharged) of SARS-CoV (green) and SARS-CoV-2 (yellow) 3CLpros. The 2D schematic representation of each inhibitory compound was also drawn. Figures were created with Maestro v11.5.011. S1 represents the polar S1 site of 3CLpros; S2 for the hydrophobic S2 site. The pink arrows represent hydrogen bond interaction, the blue dot line is for π–π stacking and the green line is for salt bridge.
See this image and copyright information in PMC

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