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Drug Res (Stuttg) 2021; 71(08): 462-472
DOI: 10.1055/a-1467-5828
Original Article

Theaflavin-3’-O-gallate a Black-tea Constituent Blocked SARS CoV-2 RNA dependant RNA Polymerase Active-site with Better Docking Results than Remdesivir

Amrita Banerjee
1   Department of Biochemistry and Biotechnology, Cell and Molecular Therapeutics Laboratory Oriental Institute of Science and Technology, Midnapore, India
,
Mehak Kanwar
1   Department of Biochemistry and Biotechnology, Cell and Molecular Therapeutics Laboratory Oriental Institute of Science and Technology, Midnapore, India
,
Smarajit Maiti
1   Department of Biochemistry and Biotechnology, Cell and Molecular Therapeutics Laboratory Oriental Institute of Science and Technology, Midnapore, India
2   Founder and Secretary, Agricure Biotech Research Society, Epidemiology and Human Health Division, Midnapore, India
› Author Affiliations
Funding Department of Science and Technology, West Bengal (partial)
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Abstract

Background Replication of SARS-CoV-2 depends on viral RNA-dependent RNA-polymerase (RdRp). Remdesivir, the broad-spectrum RdRp inhibitor acts as nucleoside-analogues (NAs). Remdesivir has initially been repurposed as a promising drug against SARS-CoV-2 infection with some health hazards like liver damage, allergic reaction, low blood-pressure, and breathing-shortness, throat-swelling. In comparison, theaflavin-3’-O-gallate (TFMG), the abundant black tea component has gained importance in controlling viral infection. TFMG is a non-toxic, non-invasive, antioxidant, anticancer and antiviral molecule.

Results Here, we analyzed the inhibitory effect of theaflavin-3’-O-gallate on SARS CoV-2 RdRp in comparison with remdesivir by molecular-docking study. TFMG has been shown more potent in terms of lower Atomic-Contact-Energy (ACE) and higher occupancy of surface area; −393.97 Kcal/mol and 771.90 respectively, favoured with lower desolvation-energy; −9.2 Kcal/mol. TFMG forms more rigid electrostatic and H-bond than remdesivir. TFMG showed strong affinity to RNA primer and template and RNA passage-site of RdRp.

Conclusions TFMG can block the catalytic residue, NTP entry site, cation binding site, nsp7-nsp12 junction with binding energy of −6. 72 Kcal/mol with Ki value of 11.79, and interface domain with binding energy of −7.72 and −6.16 Kcal/mol with Ki value of 2.21 and 30.71 µM. And most importantly, TFMG shows antioxidant/anti-inflammatory/antiviral effect on human studies.

Key words

SARS CoV 2 RdRp - remdesivir - TFMG - Molecular docking - Inhibition

Supplementary Material



Publication History

Received: 11 December 2020
Received: 11 March 2021

Accepted: 22 March 2021

Article published online:
13 September 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag
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  • References

  • 1 Tay MZ, Poh CM, Rénia L. et al. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol 2020; 20: 363-374 Epub 2020 Apr 28. PMID: 32346093; PMCID: PMC7187672.
    CrossrefPubMedSearch in Google Scholar
  • 2 Ackermann M, Verleden SE, Kuehnel M. et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med 2020; 9 (383) 120-128 Epub 2020 May 21. PMID: 32437596; PMCID: PMC7412750
    CrossrefPubMedSearch in Google Scholar
  • 3 Wanchao Yin, Chunyou Mao, Xiaodong Luan. et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science 2020; 368: 1499-1504
    CrossrefPubMedSearch in Google Scholar
  • 4 Davies M, Osborne V, Lane S. et al. Remdesivir in Treatment of COVID-19: A Systematic Benefit-Risk Assessment. Drug Saf 2020; 43: 645-656
    CrossrefPubMedSearch in Google Scholar
  • 5 Wang M, Cao R, Zhang L. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30: 269-271
    CrossrefPubMedSearch in Google Scholar
  • 6 Cao YC, Deng QX, Dai SX. Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: An evaluation of the evidence.Travel Med Infect Dis 2020; 35: 101647
    PubMedSearch in Google Scholar
  • 7 Choy KT, Wong AY, Kaewpreedee P. et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res 2020; 178: 104786
    CrossrefPubMedSearch in Google Scholar
  • 8 Pardo J, Shukla AM, Chamarthi G. et al. The journey of remdesivir: From Ebola to COVID-19. Drugs in Context. 2020 9. 2020-4-14
    PubMedSearch in Google Scholar
  • 9 Jorgensen SCJ, Kebriaei R, Dresser LD. Remdesivir: Review of Pharmacology, Pre-clinical Data, and Emerging Clinical Experience for COVID-19. Pharmacotherapy 2020; 40: 659-671
    PubMedSearch in Google Scholar
  • 10 Amirian ES, Levy JK. Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses.One Health 2020; 9: 100128
    PubMedSearch in Google Scholar
  • 11 Grein J, Ohmagari N, Shin D. et al. Compassionate use of remdesivir for patients with severe covid-19. N Engl J Med 2020; 382: 2327-2336
    CrossrefPubMedSearch in Google Scholar
  • 12 Davies M, Osborne V, Lane S. et al. Remdesivir in Treatment of COVID-19: A Systematic Benefit-Risk Assessment. Drug Saf 2020; 43: 645-656
    CrossrefPubMedSearch in Google Scholar
  • 13 Wang Y, Zhou F, Zhang D. et al. Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial 2020; 21: 422 Trials. 2020. PMID: 32448345 Free PMC article.
    CrossrefPubMedSearch in Google Scholar
  • 14 Collier PD, Bryce T, Mallows R. et al. The theaflavins of black tea. Tetrahedron. 1973; 29: 125-142
    CrossrefPubMedSearch in Google Scholar
  • 15 Takino Y, Ferretti A, Flanagan V. et al. The structure of theaflavin, a polyphenol of black tea. Tetrahedron Lett 1965; 4019-4025
    PubMedSearch in Google Scholar
  • 16 Haslam E. Quinone tannin and oxidative polymerization. In Practical Polyphenolics. from Structure to Molecular Recognition and Physiological Action. Cambridge University Press; Cambridge, UK: 1998. pp 335-373
    Search in Google Scholar
  • 17 Chen C-N, Lin CP, Huang K-K. et al. Inhibition of SARS-CoV 3C-like protease activity by theaflavin-3,3'-digallate’ (TF3). Evid Based Complement Alternat Med 2005; 2: 209-215
    CrossrefPubMedSearch in Google Scholar
  • 18 Zu M, Yang F, Zhou W. et al. In vitro anti-influenza virus and anti-inflammatory activities of theaflavin derivatives. Antiviral Res 2012; 94: 217-224
    CrossrefPubMedSearch in Google Scholar
  • 19 Yang J, Li L, Jin H. et al. Vaginal gel formulation based on theaflavin derivatives as a microbicide to preventHIV sexual transmission. AIDS Res Hum Retroviruses 2012; 28: 1498-1508
    CrossrefPubMedSearch in Google Scholar
  • 20 Liu S, Lu H, Zhao Q. et al. Theaflavin derivatives in black tea and catechin derivatives in green tea inhibit HIV-1 entry by targeting gp41. Biochim Biophys Acta 2005; 1723: 270-281
    CrossrefPubMedSearch in Google Scholar
  • 21 de Oliveira A, Prince D, Lo CY. et al. Antiviral activity of theaflavin digallate against herpes simplex virus type 1. Antiviral Res 2015; 118: 56-67 Epub 2015 Mar 27. PMID: 25818500; PMCID: PMC7113870
    CrossrefPubMedSearch in Google Scholar
  • 22 Betts JW, Kelly SM, Haswell SJ. Antibacterial effects of theaflavin and synergy with epicatechin against clinical isolates of Acinetobacter baumannii and Stenotrophomonas maltophilia. Int J Antimicrob Agents 2011; 38: 421-425 Epub 2011 Aug 31. PMID: 21885260
    CrossrefPubMedSearch in Google Scholar
  • 23 Singh M, Singh R, Bhui K. et al. Tea polyphenols induce apoptosis through mitochondrial pathway and by inhibiting nuclear factor-kappaB and Akt activation in human cervical cancer cells. Oncol Res 2011; 19: 245-257
    CrossrefPubMedSearch in Google Scholar
  • 24 Venkataraman Sangita, Prasad BurraVLS, Selvarajan Ramasamy. RNA Dependent RNA Polymerses: Insights from Structure, Function and Evolution. Viruses 2018; 10: 76
    CrossrefPubMedSearch in Google Scholar
  • 25 Castro C, Arnold JJ, Cameron CE. Incorporation fidelity of the viral RNA-dependent RNA polymerase: a kinetic, thermodynamic and structural perspective. Virus Res 2005; 107: 141-149
    CrossrefPubMedSearch in Google Scholar
  • 26 Gao Y, Yan L, Huang Y. et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science 2020; 368: 779-782
    CrossrefPubMedSearch in Google Scholar
  • 27 Morris GM, Huey R, Lindstrom W. et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009; 30: 2785
    CrossrefPubMedSearch in Google Scholar
  • 28 Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31: 455-461
    CrossrefPubMedSearch in Google Scholar
  • 29 Schneidman-Duhovny D, Inbar Y, Nussinov R. et al. PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res 2005; 33 (Web Server issue) W363-W367
    CrossrefPubMedSearch in Google Scholar
  • 30 Gordon CalvinJ, Tchesnokov EgorP, Woolner Emma. et al. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency 2020; 295: 6785-6797 Epub 2020 Apr 13
    CrossrefPubMedSearch in Google Scholar
  • 31 Chowdhury P, Sahuc ME, Rouillé Y. et al. Theaflavins, polyphels of black tea, inhibit entry of hepatitis C virus in cell culture. PLoS One 2018; 13: e0198226 Published 2018 Nov 28
    CrossrefPubMedSearch in Google Scholar
  • 32 Ohba M, Oka T, Ando T. et al. Antiviral effect of theaflavins against caliciviruses. J Antibiot (Tokyo) 2017; 70: 443-447
    CrossrefPubMedSearch in Google Scholar
  • 33 Isaacs CE, Xu W. Theaflavin-3,3'-digallate and lactic acid combinations reduce herpes simplex virus infectivity. Antimicrob Agents Chemother 2013; 57: 3806-3814
    CrossrefPubMedSearch in Google Scholar
  • 34 Deganutti Giuseppe, Zhukov Andrei, Deflorian Francesca. et al. Impact of protein-ligand solvation and desolvation on transition state thermodynamic properties of adenosine A 2A ligand binding kinetics In Silico Pharmacol 2017; 20 (05) 16 eCollection 2017
    CrossrefPubMedSearch in Google Scholar
  • 35 He Hua-Feng. Research progress on theaflavins: efficacy, formation, and preparation. Food Nutr Res 2017; 61: 1344521 eCollection 2017
    CrossrefPubMedSearch in Google Scholar
  • 36 Leung LK, Su Y, Chen R. et al. Theaflavins in black tea and catechins in green tea are equally effective antioxidants. J Nutr 2001; 131: 2248-2251 PMID: 11533262
    CrossrefPubMedSearch in Google Scholar
  • 37 Su YL, Leung LK, Huang Y. et al. Stability of tea thea-flavins and catechins. Food Chem 2003; 83: 189-195
    CrossrefPubMedSearch in Google Scholar
  • 38 Takino Y, Imagawa H, Horikawa H. et al. Studies on the mechanism of the oxidation of tea leaf catechins. Part III. Formation of a reddish orange pigment and its spectral relationship to some benzotropolone derivatives. Agric Biol Chem 1964; 28: 64-71
    CrossrefPubMedSearch in Google Scholar
  • 39 Takino Y, Ferretti A, Flanagan V. et al. The structure of theaflavin, a polyphenol of black tea. Tetrahedron Lett 1965; 4019-4025
    CrossrefPubMedSearch in Google Scholar
  • 40 Tanaka T, Betsumiya Y, Mine C. Kouno I. Theanaphthoquinone, a novel pigment oxidatively derived from theaflavin during tea-fermentation. Chem Commun 2000; 1365-1366
    CrossrefPubMedSearch in Google Scholar
  • 41 Jhoo JW, Lo CY, Li S. et al. Stability of black tea polyphenol, theaflavin, and identification of theanaphthoquinone as its major radical reaction product. J Agric Food Chem 2005; 53: 6146-6150
    CrossrefPubMedSearch in Google Scholar
  • 42 Menet MC, Sang S, Yang CS. et al. Analysis of theaflavins and thearubigins from black tea extract by MALDI-TOF mass spectrometry. J Agric Food Chem 2004; 52: 2455-2461
    CrossrefPubMedSearch in Google Scholar
  • 43 Li M, Hagerman AE. Role of the flavan-3-ol and galloyl moieties in the interaction of (-)-epigallocatechin gallate with serum albumin. J Agric Food Chem 2014; 62: 3768-3775 Epub 2014 Apr 18. Erratum in: J Agric Food Chem. 2015 Dec 16;63(49):10727. PMID: 24712545; PMCID: PMC4010290
    CrossrefPubMedSearch in Google Scholar
  • 44 Sirk TW, Friedman M, Brown EF. Molecular binding of black tea theaflavins to biological membranes: relationship to bioactivities. J Agric Food Chem 2011; 59: 3780-3787
    CrossrefPubMedSearch in Google Scholar
  • 45 Sheahan TP, Sims AC, Leist SR. et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020; 11: 222 PMID: 31924756; PMCID: PMC6954302
    CrossrefPubMedSearch in Google Scholar
  • 46 Shannon A, Le NT, Selisko B. et al. Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites. Antiviral Res 2020; 178: 104793 Epub 2020 Apr 10. PMID: 32283108; PMCID: PMC7151495
    CrossrefPubMedSearch in Google Scholar
  • 47 Li Z, Wang X, Cao D. et al. Rapid review for the anti-coronavirus effect of remdesivir. Drug DiscovTher 2020; 14: 73-76 PMID: 32378648
    CrossrefPubMedSearch in Google Scholar
  • 48 Durante-Mangoni E, Andini R, Bertolino L. et al. Early experience with remdesivir in SARS-CoV-2 pneumonia. Infection 2020; 48: 779-782 Epub 2020 May 16. PMID: 32418190; PMCID: PMC7229436
    CrossrefPubMedSearch in Google Scholar
  • 49 Maiti S, Acharyya N, Ghosh TK. et al. Green Tea (Camellia sinensis) Protects Against Arsenic Neurotoxicity via Antioxidative Mechanism and Activation of Superoxide Dismutase Activity. Cent Nerv Syst Agents Med Chem 2017; 17: 187-195 PMID: 28155600
    CrossrefPubMedSearch in Google Scholar
  • 50 Acharyya N, Chattopadhyay S, Maiti S. Chemoprevention against arsenic-induced mutagenic DNA breakage and apoptotic liver damage in rat via antioxidant and SOD1 upregulation by green tea (Camellia sinensis) which recovers broken DNA resulted from arsenic-H2O2 related in vitro oxidant stress. J Environ Sci Health C Environ CarcinogEcotoxicol Rev 2014; 32: 338-361 PMID: 25436473
    CrossrefPubMedSearch in Google Scholar
  • 51 Acharyya N, Sajed Ali S, Deb B. et al. Green tea (Camellia sinensis) alleviates arsenic-induced damages to DNA and intestinal tissues in rat and in situ intestinal loop by reinforcing antioxidant system. Environ Toxicol 2015; 30: 1033-1044 Epub 2014 Mar 11 PMID: 24615952
    CrossrefPubMedSearch in Google Scholar
  • 52 Maiti S, Nazmeen A, Medda N. et al. Flavonoids green tea against oxidant stress and inflammation with related human diseases VOLUME 24, P1-14, APRIL 01 2019;
    CrossrefPubMed
  • 53 Medda N, Patra R, Ghosh TK. et al. Neurotoxic Mechanism of Arsenic: Synergistic Effect of Mitochondrial Instability, Oxidative Stress, and Hormonal-Neurotransmitter Impairment. Biol Trace Elem Res 2020; 198: 8-15 Epub 2020 Jan 14. PMID: 31939057
    CrossrefPubMedSearch in Google Scholar