Oridonin Inhibits SARS‐CoV‐2 by Targeting Its 3C‐Like Protease

Zhong, Baisen; Peng, Wanyue; Du, Shan; Chen, Bingyi; Feng, Yajuan; Hu, Xinfeng; Lai, Qi; Liu, Shujie; Zhou, Zhongwei; Fang, Pengfei; Wu, Yan; Gao, Feng; Zhou, Huihao; Sun, Litao

doi:10.1002/smsc.202100124

Cited by 22 publications

(13 citation statements)

References 36 publications

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“…Here, we screened a compound with significant inhibitory activity against EV71 3C pro based on a library of traditional Chinese medicine monomer compounds, SA. And, SA with its structural analogue (−)-Epigallocatechin gallate (EGCG) was reported to have significant inhibitory effect on SARS-CoV-2 Frontiers in Pharmacology frontiersin.org 3C pro (Supplementary Figure S4) (Zhong et al, 2022). Also, the predicted targets of SA using SwissTargetPrediction showed that the protease was the predominant target of SA action (Supplementary Figure S5), and these results further support the molecular mechanism of SA as a viral protease inhibitor.…”

Section: Discussionmentioning

confidence: 57%

Computational and experimental studies of salvianolic acid A targets 3C protease to inhibit enterovirus 71 infection

Shi

Xie²,

Ma³

et al. 2023

Front. Pharmacol.

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Hand, foot, and mouth disease (HFMD) is a common childhood infectious disease caused by enterovirus (EV) infection. EV71 is one of the major pathogens causing hand, foot, and mouth disease and is more likely to cause exacerbation and death than other enteroviruses. Although a monovalent vaccine for EV71 has been developed, there are no clinically available anti-EV71 specific drugs. Here, we performed virtual screening and biological experiments based on the traditional Chinese medicine monomer library. We identified a traditional Chinese medicine monomer, Salvianolic acid A (SA), a polyphenolic compound isolated from Salvia miltiorrhiza. Salvianolic acid A inhibits EV71 virus infection in a concentration-dependent manner, and its antiviral activity is higher than that of other reported natural polyphenols and has a high biosafety. Furthermore, molecular dynamics simulations showed that salvianolic acid A can anchor to E71, a member of the enzyme catalytic triad, and cause H40 to move away from the catalytic center. Meanwhile, molecular mechanics generalized born surface area (MMGBSA) and steered molecular dynamics (SMD) results showed that the P1 group of SA was most easily unbound to the S1 pocket of 3Cpro, which provided theoretical support to further improve the affinity of salvianolic acid A with 3Cpro. These findings suggest that salvianolic acid A is a novel EV71 3Cpro inhibitor with excellent antiviral activity and is a promising candidate for clinical studies.

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Section: Discussionmentioning

confidence: 57%

Computational and experimental studies of salvianolic acid A targets 3C protease to inhibit enterovirus 71 infection

Shi

Xie²,

Ma³

et al. 2023

Front. Pharmacol.

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“…409 Paclitaxel also increases the alveolar capillary membrane permeability, resulting in several adverse effects, including pulmonary diffusion dysfunction, which raises concerns for COVID-19 treatment. 410 Other diterpenoids, including triptolide, 411 oridonin, 412 , 413 and carnosic acid, 414 , 415 were also identified to have anti-SARS-CoV-2 activities by computational methods.…”

Section: Structures Of Small Molecule Drugs For Covid-19 Therapymentioning

confidence: 99%

Small molecules in the treatment of COVID-19

Lei

Chen

Jin

et al. 2022

Sig Transduct Target Ther

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The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies and economies. Until now, effective therapeutics against COVID-19 are in high demand. Along with our improved understanding of the structure, function, and pathogenic process of SARS-CoV-2, many small molecules with potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition of viral proteins such as RdRp and Mpro, interference of host enzymes including ACE2 and proteases, and blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, and NLRP3 pathways, are regarded feasible in drug development. The development of small molecules to treat COVID-19 has been achieved by several strategies, including computer-aided lead compound design and screening, natural product discovery, drug repurposing, and combination therapy. Several small molecules representative by remdesivir and paxlovid have been proved or authorized emergency use in many countries. And many candidates have entered clinical-trial stage. Nevertheless, due to the epidemiological features and variability issues of SARS-CoV-2, it is necessary to continue exploring novel strategies against COVID-19. This review discusses the current findings in the development of small molecules for COVID-19 treatment. Moreover, their detailed mechanism of action, chemical structures, and preclinical and clinical efficacies are discussed.

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“…These compounds possess catechol or Michael receptors that have the ability to covalently bind to the cysteine residues in SARS-CoV-2 M pro . 15,16,23,24 In this work, a practical strategy for rapidly discovering irreversible inhibitors of SARS-CoV-2 M pro from complex components (such as herbal extracts or compound prescriptions) was demonstrated. Our approach integrates target-based high-throughput screening and mass spectrometry (MS)-based approaches, enabling efficient screening of the herbal medicines with potent time-dependent inhibition on SARS-CoV-2 M pro and to rapidly identify the covalent M pro inhibitors from crude herbal extract (Figure 1).…”

Section: Several Virus-based and Host-based Targets Have Been Validatedmentioning

confidence: 99%

Discovery of the covalent SARS‐CoV‐2 M^pro inhibitors from antiviral herbs via integrating target‐based high‐throughput screening and chemoproteomic approaches

Zhang,

Zhu,

Liu

et al. 2023

Journal of Medical Virology

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The main proteases (Mpro) are highly conserved cysteine‐rich proteins that can be covalently modified by numerous natural and synthetic compounds. Herein, we constructed an integrative approach to efficiently discover covalent inhibitors of Mpro from complex herbal matrices. This work begins with biological screening of 60 clinically used antiviral herbal medicines, among which Lonicera japonica Flos (LJF) demonstrated the strongest anti‐Mpro effect (IC50 = 37.82 μg/mL). Mass spectrometry (MS)‐based chemical analysis and chemoproteomic profiling revealed that LJF extract contains at least 50 constituents, of which 22 exhibited the capability to covalently modify Mpro. We subsequently verified the anti‐Mpro effects of these covalent binders. Gallic acid and quercetin were found to potently inhibit severe acute respiratory syndrome coronavirus 2 Mpro in dose‐ and time‐ dependent manners, with the IC50 values below 10 µM. The inactivation kinetics, binding affinity and binding mode of gallic acid and quercetin were further characterized by fluorescence resonance energy transfer, surface plasmon resonance, and covalent docking simulations. Overall, this study established a practical approach for efficiently discovering the covalent inhibitors of Mpro from herbal medicines by integrating target‐based high‐throughput screening and MS‐based assays, which would greatly facilitate the discovery of key antiviral constituents from medicinal plants.

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Oridonin Inhibits SARS‐CoV‐2 by Targeting Its 3C‐Like Protease

Cited by 22 publications

References 36 publications

Computational and experimental studies of salvianolic acid A targets 3C protease to inhibit enterovirus 71 infection

Computational and experimental studies of salvianolic acid A targets 3C protease to inhibit enterovirus 71 infection

Small molecules in the treatment of COVID-19

Discovery of the covalent SARS‐CoV‐2 M^pro inhibitors from antiviral herbs via integrating target‐based high‐throughput screening and chemoproteomic approaches

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Oridonin Inhibits SARS‐CoV‐2 by Targeting Its 3C‐Like Protease

Cited by 22 publications

References 36 publications

Computational and experimental studies of salvianolic acid A targets 3C protease to inhibit enterovirus 71 infection

Computational and experimental studies of salvianolic acid A targets 3C protease to inhibit enterovirus 71 infection

Small molecules in the treatment of COVID-19

Discovery of the covalent SARS‐CoV‐2 Mpro inhibitors from antiviral herbs via integrating target‐based high‐throughput screening and chemoproteomic approaches

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Product

Resources

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Discovery of the covalent SARS‐CoV‐2 M^pro inhibitors from antiviral herbs via integrating target‐based high‐throughput screening and chemoproteomic approaches