Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2

Yeh Chen, Wen-Hao Yang, Hsiao-Fan Chen, Li-Min Huang, Jing-Yan Gao, Cheng-Wen Lin, Yu-Chuan Wang, Chia-Shin Yang, Yi-Liang Liu, Mei-Hui Hou, Chia-Ling Tsai, Yi-Zhen Chou, Bao-Yue Huang, Chian-Fang Hung, Yu-Lin Hung, Wei-Jan Wang, Wen-Chi Su, Vathan Kumar, Yu-Chieh Wu, Shih-Wei Chao, Chih-Shiang Chang, Jin-Shing Chen, Yu-Ping Chiang, Der-Yang Cho, Long-Bin Jeng, Chang-Hai Tsai, Mien-Chie Hung, Yeh Chen, Wen-Hao Yang, Hsiao-Fan Chen, Li-Min Huang, Jing-Yan Gao, Cheng-Wen Lin, Yu-Chuan Wang, Chia-Shin Yang, Yi-Liang Liu, Mei-Hui Hou, Chia-Ling Tsai, Yi-Zhen Chou, Bao-Yue Huang, Chian-Fang Hung, Yu-Lin Hung, Wei-Jan Wang, Wen-Chi Su, Vathan Kumar, Yu-Chieh Wu, Shih-Wei Chao, Chih-Shiang Chang, Jin-Shing Chen, Yu-Ping Chiang, Der-Yang Cho, Long-Bin Jeng, Chang-Hai Tsai, Mien-Chie Hung

Abstract

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has severely affected human lives around the world as well as the global economy. Therefore, effective treatments against COVID-19 are urgently needed. Here, we screened a library containing Food and Drug Administration (FDA)-approved compounds to identify drugs that could target the SARS-CoV-2 main protease (Mpro), which is indispensable for viral protein maturation and regard as an important therapeutic target. We identified antimalarial drug tafenoquine (TFQ), which is approved for radical cure of Plasmodium vivax and malaria prophylaxis, as a top candidate to inhibit Mpro protease activity. The crystal structure of SARS-CoV-2 Mpro in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate-binding pocket of Mpro by altering the loop region (residues 139-144) near the catalytic Cys145, which could block the catalysis of its peptide substrates. We also found that TFQ inhibited human transmembrane protease serine 2 (TMPRSS2). Furthermore, one TFQ derivative, compound 7, showed a better therapeutic index than TFQ on TMPRSS2 and may therefore inhibit the infectibility of SARS-CoV-2, including that of several mutant variants. These results suggest new potential strategies to block infection of SARS-CoV-2 and rising variants.

Keywords: COVID-19; SARS-CoV-2; TMPRSS2; drug action; drug design; drug discovery; main protease; tafenoquine; viral protease; virus entry.

Conflict of interest statement

Conflict of interest The authors declare that there is no conflict of interests with the contents of this article.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
TFQ efficiently inhibits SARS-CoV-2 Mpro.A, screening of a library of FDA-approved compounds against SARS-CoV-2 Mpro by FRET assay. Each compound (60 μM) was pre-incubated with 4 μM of SARS-CoV-2 Mpro for 30 min at room temperature. Fluorescent protein substrate (20 μM) was then added to initiate the reaction. The relative enzymatic activity of SARS-CoV-2 Mpro is shown. B, dose–response curve of TFQ against SARS-CoV-2 Mpro with an IC50 value of 31.8 μM. Data are shown as mean ± standard deviation, n = 3 technical replicates. C, melting curves of SARS-CoV-2 Mpro at various concentrations of TFQ (0, 15, 45, 60, 90 μM). D, melting curves of SARS-CoV-2 Mpro at various concentration of HCQ (0, 15, 45, 60, 90 μM). FRET, fluorescence resonance energy transfer; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TFQ, tafenoquine.
Figure 2
Figure 2
Inhibition of enzymatic activity of SARS-CoV-2 Mproby TFQ.A, analytical ultracentrifugation (AUC) experiment of SARS-CoV-2 Mpro in the presence of different concentrations of TFQ (0, 50, 60, 70, 80, 90 μM). B, comparison of the enzymatic activity of SARS-CoV-2 Mpro with the far-UV CD signals (molar ellipticity at 222 nm) by increasing dose of TFQ. The results are shown as a solid line (CD signals) or dashed line (enzyme activity measured by FRET) with error bars from at least two replicates. C, limited proteolysis of SARS-CoV-2 Mpro by trypsin in the presence of different concentrations of TFQ (left) or HCQ (right) (0, 30, 60, 90 μM). CD, circular dichroism; FRET, fluorescence resonance energy transfer; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TFQ, tafenoquine.
Figure 3
Figure 3
Structural analysis of TFQ interaction with SARS-CoV-2 Mpro.A, surface presentation of potential substrate-binding pocket of SARS-CoV-2 Mpro with TFQ. TFQ (green stick) interact with SARS-CoV-2 Mpro by forming hydrogen bonds (black dash line) on several residues (yellow stick) on SARS-CoV-2 Mpro. The S2 and S1 subsites of SARS-CoV-2 Mpro are indicated. B, detailed hydrophobic interactions between TFQ (green) and the active-site residues of SARS-CoV-2 Mpro (yellow). C, structural comparison of ligand-free form (orange) and TFQ bound form (green) of SARS-CoV-2 Mpro. The largest structural changes induced by TFQ binding occurring at the loop region containing residues 139 to 144 and indicated by black arrows. D, the detailed view of the altered loop region (residues 139–144) in (C). The potential steric clash between TFQ and the residue N142 from ligand-free form of SARS-CoV-2 Mpro is highlighted by a dashed black circle. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TFQ, tafenoquine
Figure 4
Figure 4
TFQ represses SARS-CoV-2 infection in Vero E6 cells.A, a schematic illustrating two methods of treatments of TFQ in SARS-CoV-2 infected Vero E6 cells. In the posttreatment group, cells were treated with TFQ after viral infection. In the full-time treatment group, cells were pretreated with TFQ for 1 h prior to viral infection plus the posttreatment of TFQ after viral infection. B, the virus-infected Vero E6 cells were treated with TFQ (2.5 and 5 μM) or DMSO. The cell supernatant was collected on day 1, day 2, and day 3 and then subjected to qRT-PCR to determine the viral titer (n = 3). Data are shown as mean ± standard deviation. C, the inhibition rate of virus infection on day 2 in Vero E6 cells treated with 2.5 or 5 μM TFQ with full-time or posttreatment (n = 3). Data are shown as mean ± standard deviation. D, 10 × phase-contrast images of virus-infected Vero E6 treated with DMSO or TFQ (2.5 μM and 5 μM) with TFQ full-time or posttreatment at 3 days post infection. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TFQ, tafenoquine.
Figure 5
Figure 5
TFQ derivative Compound 7 exhibits a lower toxicity than that of TFQ.A, MTT assay of VeroE6 cells (left panel) and Calu3 cells (right panel) treated for 24 h with indicated concentrations of compound 3, 7, 8, 13, and 14. Each data point represents the average of values obtained in three independent experiments. Error bars represent the standard deviation of the means. B, the CC50 values of compounds 3, 7, 8, 13, and 14 were determined by using GraphPad PRISM software and expressed as mean ± SD. C, VeroE6 and Calu3 cells were treated with varying concentrations of TFQ or compound 7, and cell viability was assessed by MTT assay. Error bars represent the standard deviation of the means. D, the CC50 values of TFQ and compound 7 were determined by using GraphPad PRISM software and expressed as mean ± SD. E, the chemical structure of TFQ and compound 7 was presented. TFQ, tafenoquine.
Figure 6
Figure 6
Compound 7 suppressed SARS-CoV-2 pseudovirus infection by TMPRSS2-dependent manner.A, immunoblot analysis of whole-cell lysates from vector control or TMPRSS2-expressing VeroE6 and Calu3 cells. B, Calu3 and VeroE6 cells with and without TMPRSS2 expression were pretreated with HCQ, TFQ or compound 7 and then infected with SARS-CoV-2 Spike pseudovirus. After 24 h of infection, the infection efficiency rate was measured by luciferase activities. Error bars represent the standard deviation of the means. C, the EC50 of TFQ and compound 7 was determined by GraphPad PRISM software, expressed as mean ± SD. D, the selectivity index (SI) of TFQ and compound 7 was measured by mean CC50/mean EC50. E and F, VeroE6 cells with TMPRSS2 expression were pretreated with indicated concentration of TFQ or compound 7 and then infected with SARS-CoV-2 Spike Wild-type, B1.1.7 B.1.351, B1.617, or B1.618 pseudovirus. After 24 h of the infection, the infection efficiency rate was measured according to luciferase activities. Error bars represent the standard deviation of the means. G and H, the EC50 (mean ± SD) and SI value of TFQ and compound 7 were determined. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TFQ, tafenoquine. TMPRSS2, TFQ inhibited human transmembrane protease serine 2.

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Source: PubMed

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