Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients
Open accessAbstract
Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and there is no cure currently. The 3CL protease (3CLpro) is a highly conserved protease which is indispensable for CoVs replication, and is a promising target for development of broad-spectrum antiviral drugs. In this study we investigated the anti-SARS-CoV-2 potential of Shuanghuanglian preparation, a Chinese traditional patent medicine with a long history for treating respiratory tract infection in China. We showed that either the oral liquid of Shuanghuanglian, the lyophilized powder of Shuanghuanglian for injection or their bioactive components dose-dependently inhibited SARS-CoV-2 3CLpro as well as the replication of SARS-CoV-2 in Vero E6 cells. Baicalin and baicalein, two ingredients of Shuanghuanglian, were characterized as the first noncovalent, nonpeptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography was distinctly different from those of known 3CLpro inhibitors. Baicalein was productively ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a "shield" in front of the catalytic dyad to effectively prevent substrate access to the catalytic dyad within the active site. Overall, this study provides an example for exploring the in vitro potency of Chinese traditional patent medicines and effectively identifying bioactive ingredients toward a specific target, and gains evidence supporting the in vivo studies of Shuanghuanglian oral liquid as well as two natural products for COVID-19 treatment.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Informed estimations of relative binding affinities can be made by fitting the intensity ratio of bound and unbound protein as a function of ligand concentration.
“Nevertheless, informed estimations can be made about relative binding affinities by fitting the intensity ratio of bound and unbound protein as a function of ligand concentration21,72.”
From Native metabolomics identifies the rivulariapeptolide family of protease inhibitors (2022) · cites this paper as [21]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
<i>Coot</i> : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571 · see citing works
A pneumonia outbreak associated with a new coronavirus of probable bat origin
Zhou, P., Yang, X.-L., Wang, X.-G., Hu, B., Zhang, L., Zhang, W., Si, H.-R., Zhu, Y., Li, B., Huang, C.-L., et al. (2020) · Nature · doi:10.1038/s41586-020-2012-7 · Cited by 21,969 · see citing works
Self-citation<i>Phaser</i> crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia
Li, Q., Guan, X., Wu, P., Wang, X., Zhou, L., Tong, Y., Ren, R., Leung, K. S. M., Lau, E. H. Y., Wong, J. Y., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2001316 · Cited by 16,575 · see citing works
Self-citationAn interactive web-based dashboard to track COVID-19 in real time
Dong, E., Du, H., & Gardner, L. (2020) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(20)30120-1 · Cited by 10,048 · see citing works
Chan, J., Yuan, S.-F., Kok, K.-H., To, K., Chu, H., Yang, J., Xing, F., Liu, J.-L., Yip, C., Poon, R., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30154-9 · Cited by 8,450 · see citing works
Self-citationStructure of Mpro from SARS-CoV-2 and discovery of its inhibitors
Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., Peng, C., et al. (2020) · Nature · doi:10.1038/s41586-020-2223-y · Cited by 4,432 · see citing works
Self-citation<i>PHENIX</i> : building new software for automated crystallographic structure determination
Adams, P. D., Grosse-Kunstleve, R. W., Hung, L.-W., Ioerger, T. R., McCoy, A. J., Moriarty, N. W., Read, R. J., Sacchettini, J. C., Sauter, N. K., & Terwilliger, T. C. (2002) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444902016657 · Cited by 4,361 · see citing works
SARS and MERS: recent insights into emerging coronaviruses
de Wit, E., van Doremalen, N., Falzarano, D., & Munster, V. J. (2016) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2016.81 · Cited by 3,510 · see citing works
Minor, W., Cymborowski, M., Otwinowski, Z., & Chruszcz, M. (2006) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444906019949 · Cited by 2,118 · see citing works
Liu, J., Cao, R., Xu, M., Wang, X., Zhang, H., Hu, H., Li, Y., Hú, Z., Zhong, W., & Wang, M. (2020) · Cell Discovery · doi:10.1038/s41421-020-0156-0 · Cited by 2,070 · see citing works
Self-citationCoronavirus Main Proteinase (3CL pro ) Structure: Basis for Design of Anti-SARS Drugs
Anand, K., Ziebuhr, J., Wadhwani, P., Mesters, J. R., & Hilgenfeld, R. (2003) · Science · doi:10.1126/science.1085658 · Cited by 1,734 · see citing works
Coronaviruses — drug discovery and therapeutic options
Zumla, A. I., Chan, J. F., Azhar, E. I., Hui, D. S. C., & Yuen, K. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.37 · Cited by 1,689 · see citing works
Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease
Dai, W., Zhang, B., Jiang, X.-M., Su, H., Li, J., Zhao, Y., Xie, X., Jin, Z., Peng, J., Liu, F., et al. (2020) · Science · doi:10.1126/science.abb4489 · Cited by 1,514 · see citing works
Self-citationPillaiyar, T., Manickam, M., Namasivayam, V., Hayashi, Y., & Jung, S. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01461 · Cited by 773 · see citing works
Design of Wide-Spectrum Inhibitors Targeting Coronavirus Main Proteases
Yang, H., Xie, W., Xue, X., Yang, K., Ma, J., Liang, W., Zhao, Q., Zhou, Z., Pei, D., Ziebuhr, J., et al. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030324 · Cited by 722 · see citing works
Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders
Dinda, B., Dinda, S., DasSharma, S., Banik, R., Chakraborty, A., & Dinda, M. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.03.004 · Cited by 545 · see citing works
SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity
Muramatsu, T., Takemoto, C., Kim, Y.-T., Wang, H., Nishii, W., Terada, T., Shirouzu, M., & Yokoyama, S. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1601327113 · Cited by 275 · see citing works
Upgrade of macromolecular crystallography beamline BL17U1 at SSRF
Wang, Q., Zhang, K., Cui, Y., Wang, Z., Pan, Q.-Y., Liu, K., Sun, B., Zhou, H., Li, M.-J., Xu, Q. L., et al. (2018) · Nuclear Science and Techniques · doi:10.1007/s41365-018-0398-9 · Cited by 263 · see citing works
Self-citationDing, Y., Cao, Z., Cao, L., et al. (2017) · Scientific Reports · doi:10.1038/srep45723 · Cited by 214 · see citing works
Jacobs, J., Grum-Tokars, V. L., Zhou, Y., Turlington, M., Saldanha, S. A., Chase, P. S., Eggler, A. L., Dawson, E. S., Báez-Santos, Y. M., Tomar, S., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm301580n · Cited by 207 · see citing works
Li, M., Shi, A., Pang, H., et al. (2014) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2014.08.031 · Cited by 192 · see citing works
Self-citationTan, J., Verschueren, K. H. G., Anand, K., Shen, J., Yang, M., Xu, Y., Rao, Z., Bigalke, J. M., Heisen, B. C., Mesters, J. R., et al. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.09.012 · Cited by 181 · see citing works
Self-citationSynthesis and evaluation of isatin derivatives as effective SARS coronavirus 3CL protease inhibitors
Chen, L.-R., Wang, Y.-C., Lin, Y., Chou, S., Chen, S., Liu, L. T., Wu, Y., Kuo, C., Chen, T. S.-S., & Juang, S. (2005) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2005.04.027 · Cited by 181 · see citing works
Self-citationGhosh, A. K., Takayama, J., Aubin, Y., Ratia, K. M., Chaudhuri, R., Báez-Santos, Y. M., Sleeman, K., Coughlin, M. M., Nichols, D. B., Mulhearn, D. C., et al. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm900611t · Cited by 134 · see citing works
Ni, L., Zhou, L., Zhou, M., Zhao, J., & Wang, D. W. (2020) · Frontiers of Medicine · doi:10.1007/s11684-020-0757-x · Cited by 122 · see citing works
Self-citationLaw, A. H. Y., Yang, C. L.-H., Lau, A. S. Y., et al. (2017) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2017.07.015 · Cited by 100 · see citing works
Liang, S., Deng, X., Lei, L., Zheng, Y., Ai, J., Chen, L., Xiong, H. Y., Mei, Z., Cheng, Y., & Ren, Y. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01466 · Cited by 96 · see citing works
Baicalin and its aglycone: a novel approach for treatment of metabolic disorders
Fang, P., Yu, M., Shi, M., Bo, P., Gu, X., & Zhang, Z. (2020) · Pharmacological Reports · doi:10.1007/s43440-019-00024-x · Cited by 83 · see citing works
Woods, L. A., Dolezal, O., Ren, B., Ryan, J. H., Peat, T. S., & Poulsen, S. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01940 · Cited by 62 · see citing works
Chemistry and pharmacology of the herb pair Flos Lonicerae japonicae-Forsythiae fructus
Guo, Y., Lin, L., & Wang, Y. (2015) · Chinese Medicine · doi:10.1186/s13020-015-0044-y · Cited by 56 · see citing works
Comment on The Ecstasy and Agony of Assay Interference Compounds
Kenny, P. W. (2017) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.7b00313 · Cited by 43 · see citing works
Tang, Y., Wang, Z., Huo, C., et al. (2018) · Microbial Pathogenesis · doi:10.1016/j.micpath.2018.06.004 · Cited by 42 · see citing works
Zhang, J., Huitema, C., Niu, C., et al. (2008) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2008.01.001 · Cited by 41 · see citing works
Zhang, F., Xie, Z.-N., Tang, X., et al. (2018) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2018.03.066 · Cited by 34 · see citing works
Shuang-Huang-Lian injection induces an immediate hypersensitivity reaction via C5a but not IgE
Gao, Y., Hou, R., Han, Y., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-21843-7 · Cited by 33 · see citing works
Pedro, L., Voorhis, W. C. V., & Quinn, R. J. (2016) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-016-1417-x · Cited by 30 · see citing works
Ma, Q., Liang, D., Song, S., et al. (2017) · Viruses · doi:10.3390/v9040079 · Cited by 30 · see citing works
Wang, Y. H., Xu, K. J., & Jiang, W. (1995) · PubMed · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
NPClassifier: A Deep Neural Network-Based Structural Classification Tool for Natural Products
Kim, H. W., Wang, M., Leber, C. A., Nothias, L.-F., Reher, R., Kang, K. B., van der Hooft, J. J. J., Dorrestein, P. C., Gerwick, W. H., & Cottrell, G. W. (2021) · Journal of Natural Products · doi:10.1021/acs.jnatprod.1c00399 · Cited by 551 · see citing works
Ma, C., Tan, H., Choza, J., Wang, Y., & Wang, J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.10.026 · Cited by 86 · see citing works
Native metabolomics identifies the rivulariapeptolide family of protease inhibitors
Reher, R., Aron, A. T., Fajtová, P., Stincone, P., Wagner, B., Pérez-Lorente, A. I., Liu, C., Shalom, I. Y. B., Bittremieux, W., Wang, M., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32016-6 · Cited by 53 · see citing works
- Authors
- Su, H.-X., Yao, S., Zhao, W.-F., Li, M.-J., Liu, J., Shang, W.-J., Xie, H., Ke, C.-Q., Hu, H.-C., Gao, M.-N., Yu, K.-Q., Liu, H., Shen, J.-S., Tang, W., Zhang, L.-K., Xiao, G.-F., Ni, L., Wang, D.-W., Zuo, J.-P., Jiang, H.-L., Bai, F., Wu, Y., Ye, Y., & Xu, Y.-C.
- Affiliations
- Chinese Academy of Sciences (CN)
- China Pharmaceutical University (CN)
- Tongji Hospital (CN)
- ShanghaiTech University (CN)
- Corresponding author
- Bai, Fang
- Wu, Yan
- Xu, Ye-chun
- Venue
- Acta Pharmacologica Sinica
- Published
- 2020-07-31
- Volume
- 41
- Issue
- 9
- Pages
- 1167-1177
- ISSN
- 0253-9756 (ISSN-L)
- 1671-4083
- 1745-7254
- PMC
- PMC7393338
- OpenAlex
- W3046385872
- Cited by
- 456
- References
- 39
- Citations by year
- 2026: 22 · 2025: 52 · 2024: 75 · 2023: 76 · 2022: 93 · 2021: 118 · 2020: 20
- FWCI
- 10.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Acta Pharmacologica Sinica (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (91953000, 21877122)
- Chinese Academy of Sciences (153631KYSB20170043)
- Science and Technology Commission of Shanghai Municipality (20431900200)
- Chinese Academy of Engineering
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
- Health Sciences › Medicine › Complementary and alternative medicine › Traditional Chinese Medicine Analysis
- Keywords
- Shuanghuanglian, SARS-CoV-2, COVID-19 pandemic, main protease, main protease inhibition, baicalein, baicalin, traditional Chinese medicine, antiviral activity, Vero E6 cells, protein crystallography, substrate binding pocket, natural products
- MeSH terms
- Betacoronavirus, COVID-19, SARS-CoV-2, Administration, Oral, Animals, Antiviral Agents, Chlorocebus aethiops, Drugs, Chinese Herbal, Flavonoids, Humans, Pneumonia, Viral, Vero Cells, Virus Replication, Coronavirus Infections, Flavanones, Enzyme Assays, Pandemics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
