Systematic Studies on the Anti-SARS-CoV-2 Mechanisms of Tea Polyphenol-Related Natural Products

Overview

Journal ACS Omega

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Jun 10

PMID 38854515

Authors

Chen-Wei Li

Tai-Ling Chao

Chin-Lan Lai

Cheng-Chin Lin

Max Yu-Chen Pan

Chieh-Ling Cheng

Chih-Jung Kuo

Lily Hui-Ching Wang

Sui-Yuan Chang

Po-Huang Liang

Affiliations

Soon will be listed here.

Abstract

The causative pathogen of COVID-19, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), utilizes the receptor-binding domain (RBD) of the spike protein to bind to human receptor angiotensin-converting enzyme 2 (ACE2). Further cleavage of spike by human proteases furin, TMPRSS2, and/or cathepsin L facilitates viral entry into the host cells for replication, where the maturation of polyproteins by 3C-like protease (3CL) and papain-like protease (PL) yields functional nonstructural proteins (NSPs) such as RNA-dependent RNA polymerase (RdRp) to synthesize mRNA of structural proteins. By testing the tea polyphenol-related natural products through various assays, we found that the active antivirals prevented SARS-CoV-2 entry by blocking the RBD/ACE2 interaction and inhibiting the relevant human proteases, although some also inhibited the viral enzymes essential for replication. Due to their multitargeting properties, these compounds were often misinterpreted for their antiviral mechanisms. In this study, we provide a systematic protocol to check and clarify their anti-SARS-CoV-2 mechanisms, which should be applicable for all of the antivirals.

Citing Articles

Diverse Structures of Tea Polyphenols from Rougui Wuyi Rock Tea and Their Potential as Inhibitor of 3C-like Protease.

Sun Q, Chen X, Zhang J, Song J, Yao L, Zhao Y Molecules. 2025; 30(5).

PMID: 40076249 PMC: 11901911. DOI: 10.3390/molecules30051024.

Green Synthesis of Tetrahydropyrazino[2,1-a:5,4-a']diisoquinolines as SARS-CoV-2 Entry Inhibitors.

Palla S, Palla S, Liu J, Chao T, Lee T, Kavala V ACS Omega. 2025; 10(1):1164-1176.

PMID: 39829498 PMC: 11740144. DOI: 10.1021/acsomega.4c08640.

Antibacterial, Antifungal, Antiviral Activity, and Mechanisms of Action of Plant Polyphenols.

Davidova S, Galabov A, Satchanska G Microorganisms. 2025; 12(12.

PMID: 39770706 PMC: 11728530. DOI: 10.3390/microorganisms12122502.

References

Ridgway H, Chasapis C, Kelaidonis K, Ligielli I, Moore G, Kate Gadanec L . Understanding the Driving Forces That Trigger Mutations in SARS-CoV-2: Mutational Energetics and the Role of Arginine Blockers in COVID-19 Therapy. Viruses. 2022; 14(5). PMC: 9143829. DOI: 10.3390/v14051029. View

Kirchdoerfer R, Ward A . Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nat Commun. 2019; 10(1):2342. PMC: 6538669. DOI: 10.1038/s41467-019-10280-3. View

Chen C, Lin C, Huang K, Chen W, Hsieh H, Liang P . Inhibition of SARS-CoV 3C-like Protease Activity by Theaflavin-3,3'-digallate (TF3). Evid Based Complement Alternat Med. 2005; 2(2):209-215. PMC: 1142193. DOI: 10.1093/ecam/neh081. View

Swiderski J, Kate Gadanec L, Apostolopoulos V, Moore G, Kelaidonis K, Matsoukas J . Role of Angiotensin II in Cardiovascular Diseases: Introducing Bisartans as a Novel Therapy for Coronavirus 2019. Biomolecules. 2023; 13(5). PMC: 10216788. DOI: 10.3390/biom13050787. View

Ip J, Chu A, Chan W, Leung R, Abdullah S, Sun Y . Global prevalence of SARS-CoV-2 3CL protease mutations associated with nirmatrelvir or ensitrelvir resistance. EBioMedicine. 2023; 91:104559. PMC: 10101811. DOI: 10.1016/j.ebiom.2023.104559. View

Takashita E, Yamayoshi S, Simon V, van Bakel H, Sordillo E, Pekosz A . Efficacy of Antibodies and Antiviral Drugs against Omicron BA.2.12.1, BA.4, and BA.5 Subvariants. N Engl J Med. 2022; 387(5):468-470. PMC: 9342381. DOI: 10.1056/NEJMc2207519. View

Subissi L, Posthuma C, Collet A, Zevenhoven-Dobbe J, Gorbalenya A, Decroly E . One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities. Proc Natl Acad Sci U S A. 2014; 111(37):E3900-9. PMC: 4169972. DOI: 10.1073/pnas.1323705111. View

Shannon A, Selisko B, Le N, Huchting J, Touret F, Piorkowski G . Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis. Nat Commun. 2020; 11(1):4682. PMC: 7499305. DOI: 10.1038/s41467-020-18463-z. View

Ksiazek T, Erdman D, Goldsmith C, Zaki S, Peret T, Emery S . A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med. 2003; 348(20):1953-66. DOI: 10.1056/NEJMoa030781. View

10.

Bertolin A, Weissmann F, Zeng J, Posse V, Milligan J, Canal B . Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp12/7/8 RNA-dependent RNA polymerase. Biochem J. 2021; 478(13):2425-2443. PMC: 8286815. DOI: 10.1042/BCJ20210200. View

11.

Chapman R, Andurkar S . A review of natural products, their effects on SARS-CoV-2 and their utility as lead compounds in the discovery of drugs for the treatment of COVID-19. Med Chem Res. 2021; 31(1):40-51. PMC: 8636070. DOI: 10.1007/s00044-021-02826-2. View

12.

Lo H, Hui K, Lai H, He X, Khan K, Kaur S . Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir. ACS Cent Sci. 2021; 7(5):792-802. PMC: 8056950. DOI: 10.1021/acscentsci.0c01186. View

13.

Ivanov K, Thiel V, Dobbe J, van der Meer Y, Snijder E, Ziebuhr J . Multiple enzymatic activities associated with severe acute respiratory syndrome coronavirus helicase. J Virol. 2004; 78(11):5619-32. PMC: 415832. DOI: 10.1128/JVI.78.11.5619-5632.2004. View

14.

Gandhi S, Klein J, Robertson A, Pena-Hernandez M, Lin M, Roychoudhury P . De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report. Nat Commun. 2022; 13(1):1547. PMC: 8930970. DOI: 10.1038/s41467-022-29104-y. View

15.

Freitas B, Durie I, Murray J, Longo J, Miller H, Crich D . Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease. ACS Infect Dis. 2020; 6(8):2099-2109. DOI: 10.1021/acsinfecdis.0c00168. View

16.

Cui X, Zhou R, Huang C, Zhang R, Wang J, Zhang Y . Identification of Theaflavin-3,3'-Digallate as a Novel Zika Virus Protease Inhibitor. Front Pharmacol. 2020; 11:514313. PMC: 7609463. DOI: 10.3389/fphar.2020.514313. View

17.

Zhu N, Zhang D, Wang W, Li X, Yang B, Song J . A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020; 382(8):727-733. PMC: 7092803. DOI: 10.1056/NEJMoa2001017. View

18.

Li G, Hilgenfeld R, Whitley R, De Clercq E . Therapeutic strategies for COVID-19: progress and lessons learned. Nat Rev Drug Discov. 2023; 22(6):449-475. PMC: 10113999. DOI: 10.1038/s41573-023-00672-y. View

19.

Islam M, Sarkar C, El-Kersh D, Jamaddar S, Uddin S, Shilpi J . Natural products and their derivatives against coronavirus: A review of the non-clinical and pre-clinical data. Phytother Res. 2020; 34(10):2471-2492. DOI: 10.1002/ptr.6700. View

20.

Lee R, Li T, Chang S, Chao T, Kuo C, Pan M . Identification of Entry Inhibitors against Delta and Omicron Variants of SARS-CoV-2. Int J Mol Sci. 2022; 23(7). PMC: 8999638. DOI: 10.3390/ijms23074050. View