Skip to main content

Advertisement

Log in

(−)-Epigallocatechin-3-gallate inhibits the replication cycle of hepatitis C virus

  • Original Article
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

(−)-Epigallocatechin-3-gallate (EGCG) is the most abundant catechin in green tea. In this study, we found that hepatitis C virus (HCV) infection was significantly suppressed by EGCG in an HCV cell culture (HCVcc) system using a JFH1-GFP chimeric virus, with a 50 % effective concentration (EC50) of 17.9 μM. The inhibitory activity of EGCG was confirmed by monitoring HCV RNA and protein expression levels in Huh7.5.1 cells infected with the JFH1 virus. Moreover, we demonstrated that the inhibitory mechanisms of EGCG were attributable to the suppression of both the HCV entry and RNA replication steps, although EGCG had little effect on translation directed by the viral internal ribosome entry site (IRES). Furthermore, HCV could be rapidly eliminated from cell cultures after two and five passages in the presence of 50 and 25 μM EGCG, respectively. These results indicate that EGCG is a potential candidate as a preventive and antiviral drug for HCV infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Ahn WS, Yoo J, Huh SW, Kim CK, Lee JM, Namkoong SE, Bae SM, Lee IP (2003) Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur J Cancer Prev 12:383–390

    Article  PubMed  Google Scholar 

  2. Babich H, Krupka ME, Nissim HA, Zuckerbraun HL (2005) Differential in vitro cytotoxicity of (−)-epicatechin gallate (ECG) to cancer and normal cells from the human oral cavity. Toxicol In Vitro 19:231–242

    Article  PubMed  CAS  Google Scholar 

  3. Baldick CJ, Wichroski MJ, Pendri A, Walsh AW, Fang J, Mazzucco CE, Pokornowski KA, Rose RE, Eggers BJ, Hsu M, Zhai W, Zhai G, Gerritz SW, Poss MA, Meanwell NA, Cockett MI, Tenney DJ (2010) A novel small molecule inhibitor of hepatitis C virus entry. PLoS Pathog 6(9):e24142

    Article  Google Scholar 

  4. Bartosch B, Dubuisson J, Cosset FL (2003) Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. J Exp Med 197:633–642

    Article  PubMed  CAS  Google Scholar 

  5. Cabrera C, Artacho R, Gimenez R (2006) Beneficial effects of green tea–a review. J Am Coll Nutr 25:79–99

    PubMed  CAS  Google Scholar 

  6. Calland N, Albecka A, Belouzard S, Wychowski C, Duverlie G, Descamps V, Hober D, Dubuisson J, Rouille Y, Seron K (2012) (−)-Epigallocatechin-3-gallate is a new inhibitor of hepatitis C virus entry. Hepatology 55:720–729

    Article  PubMed  CAS  Google Scholar 

  7. Chang LK, Wei TT, Chiu YF, Tung CP, Chuang JY, Hung SK, Li C, Liu ST (2003) Inhibition of Epstein-Barr virus lytic cycle by (−)-epigallocatechin gallate. Biochem Biophys Res Commun 301:1062–1068

    Article  PubMed  CAS  Google Scholar 

  8. Ciesek S, von Hahn T, Colpitts CC, Schang LM, Friesland M, Steinmann J, Manns MP, Ott M, Wedemeyer H, Meuleman P, Pietschmann T, Steinmann E (2011) The green tea polyphenol, epigallocatechin-3-gallate, inhibits hepatitis C virus entry. Hepatology 54:1947–1955

    Article  PubMed  CAS  Google Scholar 

  9. Crockett SD, Keeffe EB (2005) Natural history and treatment of hepatitis B virus and hepatitis C virus coinfection. Ann Clin Microbiol Antimicrob 4:13

    Article  PubMed  Google Scholar 

  10. Dona M, Dell’Aica I, Calabrese F, Benelli R, Morini M, Albini A, Garbisa S (2003) Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis. J Immunol 170:4335–4341

    PubMed  CAS  Google Scholar 

  11. Drummer HE, Maerz A, Poumbourios P (2003) Cell surface expression of functional hepatitis C virus E1 and E2 glycoproteins. FEBS Lett 546:385–390

    Article  PubMed  CAS  Google Scholar 

  12. Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun JH, O’Boyle DR 2nd, Lemm JA, Wang C, Knipe JO, Chien C, Colonno RJ, Grasela DM, Meanwell NA, Hamann LG (2010) Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465:96–100

    Article  PubMed  CAS  Google Scholar 

  13. Gonzalez O, Fontanes V, Raychaudhuri S, Loo R, Loo J, Arumugaswami V, Sun R, Dasgupta A, French SW (2009) The heat shock protein inhibitor Quercetin attenuates hepatitis C virus production. Hepatology 50:1756–1764

    Article  PubMed  CAS  Google Scholar 

  14. Goueslain L, Alsaleh K, Horellou P, Roingeard P, Descamps V, Duverlie G, Ciczora Y, Wychowski C, Dubuisson J, Rouille Y (2010) Identification of GBF1 as a cellular factor required for hepatitis C virus RNA replication. J Virol 84:773–787

    Article  PubMed  CAS  Google Scholar 

  15. Han Q, Xu C, Wu C, Zhu W, Yang R, Chen X (2009) Compensatory mutations in NS3 and NS5A proteins enhance the virus production capability of hepatitis C reporter virus. Virus Res 145:63–73

    Article  PubMed  CAS  Google Scholar 

  16. He W, Li LX, Liao QJ, Liu CL, Chen XL (2011) Epigallocatechin gallate inhibits HBV DNA synthesis in a viral replication—inducible cell line. World J Gastroenterol 17:1507–1514

    Article  PubMed  CAS  Google Scholar 

  17. Ho HY, Cheng ML, Weng SF, Leu YL, Chiu DT (2009) Antiviral effect of epigallocatechin gallate on enterovirus 71. J Agric Food Chem 57:6140–6147

    Article  PubMed  CAS  Google Scholar 

  18. Hsu M, Zhang J, Flint M, Logvinoff C, Cheng-Mayer C, Rice CM, McKeating JA (2003) Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. Proc Natl Acad Sci USA 100:7271–7276

    Article  PubMed  CAS  Google Scholar 

  19. Huang W, Ding L, Huang Q, Hu H, Liu S, Yang X, Hu X, Dang Y, Shen S, Li J, Ji X, Jiang S, Liu JO, Yu L (2010) Carbonyl reductase 1 as a novel target of (−)-epigallocatechin gallate against hepatocellular carcinoma. Hepatology 52:703–714

    Article  PubMed  CAS  Google Scholar 

  20. Isaacs CE, Wen GY, Xu W, Jia JH, Rohan L, Corbo C, Di Maggio V, Jenkins EC Jr, Hillier S (2008) Epigallocatechin gallate inactivates clinical isolates of herpes simplex virus. Antimicrob Agents Chemother 52:962–970

    Article  PubMed  CAS  Google Scholar 

  21. Jiang F, Chen W, Yi K, Wu Z, Si Y, Han W, Zhao Y (2011) The evaluation of catechins that contain a galloyl moiety as potential HIV-1 integrase inhibitors. Clin Immunol 137:347–356

    Article  Google Scholar 

  22. Kanadzu M, Lu Y, Morimoto K (2006) Dual function of (–)-epigallocatechin gallate (EGCG) in healthy human lymphocytes. Cancer Lett 241:250–255

    Article  PubMed  CAS  Google Scholar 

  23. Kato T, Date T, Murayama A, Morikawa K, Akazawa D, Wakita T (2006) Cell culture and infection system for hepatitis C virus. Nat Protoc 1:2334–2339

    Article  PubMed  CAS  Google Scholar 

  24. Kawai K, Tsuno NH, Kitayama J, Okaji Y, Yazawa K, Asakage M, Sasaki S, Watanabe T, Takahashi K, Nagawa H (2005) Epigallocatechin gallate induces apoptosis of monocytes. J Allergy Clin Immunol 115:186–191

    Article  PubMed  CAS  Google Scholar 

  25. Khan N, Afaq F, Saleem M, Ahmad N, Mukhtar H (2006) Targeting multiple signaling pathways by green tea polyphenol (−)-epigallocatechin-3-gallate. Cancer Res 66:2500–2505

    Article  PubMed  CAS  Google Scholar 

  26. Kieffer TL, Kwong AD, Picchio GR (2010) Viral resistance to specifically targeted antiviral therapies for hepatitis C (STAT-Cs). J Antimicrob Chemother 65:202–212

    Article  PubMed  CAS  Google Scholar 

  27. Kim CS, Jung JH, Wakita T, Yoon SK, Jang SK (2007) Monitoring the antiviral effect of alpha interferon on individual cells. J Virol 81:8814–8820

    Article  PubMed  CAS  Google Scholar 

  28. Kwong AD, McNair L, Jacobson I, George S (2008) Recent progress in the development of selected hepatitis C virus NS3.4A protease and NS5B polymerase inhibitors. Curr Opin Pharmacol 8:522–531

    Article  PubMed  CAS  Google Scholar 

  29. Li S, Hattori T, Kodama EN (2011) Epigallocatechin gallate inhibits the HIV reverse transcription step. Antivir Chem Chemother 21:239–243

    Article  PubMed  CAS  Google Scholar 

  30. Lindenbach BD, Evans MJ, Syder AJ, Wolk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, Rice CM (2005) Complete replication of hepatitis C virus in cell culture. Science 309:623–626

    Article  PubMed  CAS  Google Scholar 

  31. Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110–113

    Article  PubMed  CAS  Google Scholar 

  32. Moradpour D, Penin F, Rice CM (2007) Replication of hepatitis C virus. Nat Rev Microbiol 5:453–463

    Article  PubMed  CAS  Google Scholar 

  33. Muir AJ (2011) Telaprevir for the treatment of chronic hepatitis C infection. Expert Rev Anti Infect Ther 9:1105–1114

    Article  PubMed  CAS  Google Scholar 

  34. Munir S, Saleem S, Idrees M, Tariq A, Butt S, Rauff B, Hussain A, Badar S, Naudhani M, Fatima Z, Ali M, Ali L, Akram M, Aftab M, Khubaib B, Awan Z (2010) Hepatitis C treatment: current and future perspectives. Virol J 7:296

    Article  PubMed  Google Scholar 

  35. Nakagawa S, Umehara T, Matsuda C, Kuge S, Sudoh M, Kohara M (2007) Hsp90 inhibitors suppress HCV replication in replicon cells and humanized liver mice. Biochem Biophys Res Commun 353:882–888

    Article  PubMed  CAS  Google Scholar 

  36. Noda C, He J, Takano T, Tanaka C, Kondo T, Tohyama K, Yamamura H, Tohyama Y (2007) Induction of apoptosis by epigallocatechin-3-gallate in human lymphoblastoid B cells. Biochem Biophys Res Commun 362:951–957

    Article  PubMed  CAS  Google Scholar 

  37. Okamoto T, Nishimura Y, Ichimura T, Suzuki K, Miyamura T, Suzuki T, Moriishi K, Matsuura Y (2006) Hepatitis C virus RNA replication is regulated by FKBP8 and Hsp90. EMBO J 25:5015–5025

    Article  PubMed  CAS  Google Scholar 

  38. Pietschmann T, Lohmann V, Kaul A, Krieger N, Rinck G, Rutter G, Strand D, Bartenschlager R (2002) Persistent and transient replication of full-length hepatitis C virus genomes in cell culture. J Virol 76:4008–4021

    Article  PubMed  CAS  Google Scholar 

  39. Roh C, Jo SK (2011) (−)-Epigallocatechin gallate inhibits hepatitis C virus (HCV) viral protein NS5B. Talanta 85:2639–2642

    Article  PubMed  CAS  Google Scholar 

  40. Schaller T, Appel N, Koutsoudakis G, Kallis S, Lohmann V, Pietschmann T, Bartenschlager R (2007) Analysis of hepatitis C virus superinfection exclusion by using novel fluorochrome gene-tagged viral genomes. J Virol 81:4591–4603

    Article  PubMed  CAS  Google Scholar 

  41. She Y, Liao Q, Chen X, Ye L, Wu Z (2008) Hepatitis C virus (HCV) NS2 protein up-regulates HCV IRES-dependent translation and down-regulates NS5B RdRp activity. Arch Virol 153:1991–1997

    Article  PubMed  CAS  Google Scholar 

  42. Shepard CW, Finelli L, Alter MJ (2005) Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 5:558–567

    Article  PubMed  Google Scholar 

  43. Song JM, Lee KH, Seong BL (2005) Antiviral effect of catechins in green tea on influenza virus. Antiviral Res 68:66–74

    Article  PubMed  CAS  Google Scholar 

  44. Stapleton PD, Shah S, Anderson JC, Hara Y, Hamilton-Miller JM, Taylor PW (2004) Modulation of beta-lactam resistance in Staphylococcus aureus by catechins and gallates. Int J Antimicrob Agents 23:462–467

    Article  PubMed  CAS  Google Scholar 

  45. Steinmann E, Whitfield T, Kallis S, Dwek RA, Zitzmann N, Pietschmann T, Bartenschlager R (2007) Antiviral effects of amantadine and iminosugar derivatives against hepatitis C virus. Hepatology 46:330–338

    Article  PubMed  CAS  Google Scholar 

  46. Tao W, Xu C, Ding Q, Li R, Xiang Y, Chung J, Zhong J (2009) A single point mutation in E2 enhances hepatitis C virus infectivity and alters lipoprotein association of viral particles. Virology 395:67–76

    Article  PubMed  CAS  Google Scholar 

  47. Timm J, Roggendorf M (2007) Sequence diversity of hepatitis C virus: implications for immune control and therapy. World J Gastroenterol 13:4808–4817

    PubMed  CAS  Google Scholar 

  48. Tsubota A, Fujise K, Namiki Y, Tada N (2011) Peginterferon and ribavirin treatment for hepatitis C virus infection. World J Gastroenterol 17:419–432

    Article  PubMed  CAS  Google Scholar 

  49. Ullmann U, Haller J, Decourt JP, Girault N, Girault J, Richard-Caudron AS, Pineau B, Weber P (2003) A single ascending dose study of epigallocatechin gallate in healthy volunteers. J Int Med Res 31:88–101

    PubMed  CAS  Google Scholar 

  50. Verucchi G, Calza L, Manfredi R, Chiodo F (2004) Human immunodeficiency virus and hepatitis C virus coinfection: epidemiology, natural history, therapeutic options and clinical management. Infection 32:33–46

    Article  PubMed  CAS  Google Scholar 

  51. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Krausslich HG, Mizokami M, Bartenschlager R, Liang TJ (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11:791–796

    Article  PubMed  CAS  Google Scholar 

  52. Weber JM, Ruzindana-Umunyana A, Imbeault L, Sircar S (2003) Inhibition of adenovirus infection and adenain by green tea catechins. Antiviral Res 58:167–173

    Article  PubMed  CAS  Google Scholar 

  53. Wu Y, Liao Q, Yang R, Chen X, Chen X (2011) A novel luciferase and GFP dual reporter virus for rapid and convenient evaluation of hepatitis C virus replication. Virus Res 155:406–414

    Article  PubMed  CAS  Google Scholar 

  54. Xu J, Wang J, Deng F, Hu Z, Wang H (2008) Green tea extract and its major component epigallocatechin gallate inhibits hepatitis B virus in vitro. Antiviral Res 78:242–249

    Article  PubMed  CAS  Google Scholar 

  55. Yamaguchi K, Honda M, Ikigai H, Hara Y, Shimamura T (2002) Inhibitory effects of (−)-epigallocatechin gallate on the life cycle of human immunodeficiency virus type 1 (HIV-1). Antiviral Res 53:19–34

    Article  PubMed  CAS  Google Scholar 

  56. Yin Z, Henry EC, Gasiewicz TA (2009) (−)-Epigallocatechin-3-gallate is a novel Hsp90 inhibitor. Biochemistry 48:336–345

    Article  PubMed  CAS  Google Scholar 

  57. Zhong J, Gastaminza P, Cheng G, Kapadia S, Kato T, Burton DR, Wieland SF, Uprichard SL, Wakita T, Chisari FV (2005) Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci USA 102:9294–9299

    Article  PubMed  CAS  Google Scholar 

  58. Zuo G, Li Z, Chen L, Xu X (2007) Activity of compounds from Chinese herbal medicine Rhodiola kirilowii (Regel) Maxim against HCV NS3 serine protease. Antiviral Res 76:86–92

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Dr. T. Wakita (National Institute of Infectious Diseases, Japan) for providing the JFH1 plasmid, Dr. F. V. Chisari (The Scripps Research Institute, USA) for providing the Huh7.5.1 cells, Dr. C. M. Rice (Rockefeller University, USA) for providing the anti-NS5A 9E10 antibody, Dr. R. Bartenschlager (Heidelberg University, Germany) for providing the pFKI389neo/NS3-3′ plasmid and the Huh7-Lunet cells, and Dr. C.Y. Li (Henan Biotechnology Research Center, China) for providing the anti-NS3 antibody. This work was supported by the National Key Programs on Infectious Disease (2008ZX10001-002) and the Major Science and Knowledge Innovation Project of the Chinese Academy of Sciences (KSCX1-YW-10).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rong-Ge Yang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, C., Qiu, H., Gong, J. et al. (−)-Epigallocatechin-3-gallate inhibits the replication cycle of hepatitis C virus. Arch Virol 157, 1301–1312 (2012). https://doi.org/10.1007/s00705-012-1304-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-012-1304-0

Keywords

Navigation