Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CLpro

Du, Ruikun; Cooper, Laura; Chen, Zinuo; Lee, Hyun; Rong, Lijun; Cui, Qinghua

doi:10.1016/j.antiviral.2021.105075

Cited by 50 publications

(51 citation statements)

References 30 publications

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“… 13 In another study using a cell-based model and biochemical assay, ellagitannins, including chebulagic acid and PA, were reported to reduce virus-induced plaque formation in a transfected monkey kidney epithelial cell (Vero-E6) monolayer and inhibit the enzymatic activity of Mpro in an allosteric manner. 27 However, bioassays with virus-transfected cells are highly regulated and can only be conducted in appropriate physical containment facilities, such as biosafety level 3 and 4 (BSL-3 and -4) laboratories, 28 which limit the feasibility of these assay for biological evaluations. In the present study, we used a cell-free fluorescent assay to evaluate the inhibitory activity of dietary hydrolyzable tannins, including ellagitannins and gallotannins, as well as their gut microbial metabolites, on SARS-CoV-2 Mpro.…”

Section: Discussionmentioning

confidence: 99%

“… 38 , 39 In addition, it is not clear whether these tannins bind to the catalytic domain, as predicted by the molecular docking experiment 13 or the allosteric site on the enzyme protein as reported in studies using in vitro models. 27 These shortcomings may be overcome by utilizing complementary experimental methods, including competitive binding assays and/or X-ray crystal work.…”

Section: Discussionmentioning

confidence: 99%

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Inhibitory Effects and Surface Plasmon Resonance-Based Binding Affinities of Dietary Hydrolyzable Tannins and Their Gut Microbial Metabolites on SARS-CoV-2 Main Protease

Feng

Liu

et al. 2021

J. Agric. Food Chem.

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Severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (Mpro) inhibitors are considered as potential treatments for coronavirus disease 2019, and dietary polyphenols show promise in SARS-CoV-2 Mpro inhibition based on in silico studies. In the present study, we utilize a combination of biochemical-, surface plasmon resonance-, and docking-based assays to evaluate the inhibition and binding affinities of a series of tannins and their gut microbial metabolites on SARS-CoV-2 Mpro. The tested compounds (2–50 μM) were hydrolyzable tannins, including ellagitannins (punicalagin and ellagic acid) and gallotannins (tannic acid, pentagalloyl glucose, ginnalin A, and gallic acid), and their gut microbial metabolites, urolithins and pyrogallol, respectively. They inhibited SARS-CoV-2 Mpro (by 6.6–100.0% at 50 μM) and bound directly to the Mpro protein (with dissociation constants from 1.1 × 10 –6 to 5.3 × 10 –5 M). This study sheds light on the inhibitory effects of tannins and their metabolites on SARS-CoV-2 Mpro.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects and Surface Plasmon Resonance-Based Binding Affinities of Dietary Hydrolyzable Tannins and Their Gut Microbial Metabolites on SARS-CoV-2 Main Protease

Feng

Liu

et al. 2021

J. Agric. Food Chem.

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“…A catalytic water molecule is also important and makes a strong hydrogen bond with His41 [ 5 ]. Although some allosteric binding sites have been identified for the SARS-CoV-2 M-pro [ 6 , 7 , 8 , 9 ], most of the inhibitors crystallized within the M-pro bind to the active site [ 10 ]. One strategy used to find SARS-CoV-2 M-pro inhibitors, especially at the beginning of the pandemic, was drug repositioning [ 2 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

A Review of the Current Landscape of SARS-CoV-2 Main Protease Inhibitors: Have We Hit the Bullseye Yet?

Macip

Garcia-Segura

Mestres-Truyol

et al. 2021

IJMS

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In this review, we collected 1765 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M-pro inhibitors from the bibliography and other sources, such as the COVID Moonshot project and the ChEMBL database. This set of inhibitors includes only those compounds whose inhibitory capacity, mainly expressed as the half-maximal inhibitory concentration (IC50) value, against M-pro from SARS-CoV-2 has been determined. Several covalent warheads are used to treat covalent and non-covalent inhibitors separately. Chemical space, the variation of the IC50 inhibitory activity when measured by different methods or laboratories, and the influence of 1,4-dithiothreitol (DTT) are discussed. When available, we have collected the values of inhibition of viral replication measured with a cellular antiviral assay and expressed as half maximal effective concentration (EC50) values, and their possible relationship to inhibitory potency against M-pro is analyzed. Finally, the most potent covalent and non-covalent inhibitors that simultaneously inhibit the SARS-CoV-2 M-pro and the virus replication in vitro are discussed.

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“…After adding 5 µM FRET substrate, the V I was measured using a FRET assay. The inhibition mechanism of dieckol was inferred using the LB plot and a K i value was generated by its secondary plot [ 35 , 41 , 42 ].…”

Section: Methodsmentioning

confidence: 99%

Development of a simple and miniaturized sandwich-like fluorescence polarization assay for rapid screening of SARS-CoV-2 main protease inhibitors

Gao

Lin

et al. 2021

Cell Biosci

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Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmissible and has caused a pandemic named coronavirus disease 2019 (COVID-19), which has quickly spread worldwide. Although several therapeutic agents have been evaluated or approved for the treatment of COVID-19 patients, efficacious antiviral agents are still lacking. An attractive therapeutic target for SARS-CoV-2 is the main protease (Mpro), as this highly conserved enzyme plays a key role in viral polyprotein processing and genomic RNA replication. Therefore, the identification of efficacious antiviral agents against SARS-CoV-2 Mpro using a rapid, miniaturized and economical high-throughput screening (HTS) assay is of the highest importance at the present. Results In this study, we first combined the fluorescence polarization (FP) technique with biotin-avidin system (BAS) to develop a novel and step-by-step sandwich-like FP screening assay to quickly identify SARS-CoV-2 Mpro inhibitors from a natural product library. Using this screening assay, dieckol, a natural phlorotannin component extracted from a Chinese traditional medicine Ecklonia cava, was identified as a novel competitive inhibitor against SARS-CoV-2 Mpro in vitro with an IC50 value of 4.5 ± 0.4 µM. Additionally, dieckol exhibited a high affinity with SARS-CoV-2 Mpro using surface plasmon resonance (SPR) analysis and could bind to the catalytic sites of Mpro through hydrogen-bond interactions in the predicted docking model. Conclusions This innovative sandwich-like FP screening assay enables the rapid discovery of antiviral agents targeting viral proteases, and dieckol will be an excellent lead compound for generating more potent and selective antiviral agents targeting SARS-CoV-2 Mpro.

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Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CLpro

Cited by 50 publications

References 30 publications

Inhibitory Effects and Surface Plasmon Resonance-Based Binding Affinities of Dietary Hydrolyzable Tannins and Their Gut Microbial Metabolites on SARS-CoV-2 Main Protease

Inhibitory Effects and Surface Plasmon Resonance-Based Binding Affinities of Dietary Hydrolyzable Tannins and Their Gut Microbial Metabolites on SARS-CoV-2 Main Protease

A Review of the Current Landscape of SARS-CoV-2 Main Protease Inhibitors: Have We Hit the Bullseye Yet?

Development of a simple and miniaturized sandwich-like fluorescence polarization assay for rapid screening of SARS-CoV-2 main protease inhibitors

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