Antiviral Mechanism of Action of Epigallocatechin-3- O-gallate and Its Fatty Acid Esters

Kunihiro Kaihatsu, Miyuki Yamabe, Yasuhito Ebara, Kunihiro Kaihatsu, Miyuki Yamabe, Yasuhito Ebara

Abstract

Epigallocatechin-3-O-gallate (EGCG) is the major catechin component of green tea (Cameria sinensis), and is known to possess antiviral activities against a wide range of DNA viruses and RNA viruses. However, few studies have examined chemical modifications of EGCG in terms of enhanced antiviral efficacy. This paper discusses which steps of virus infection EGCG interferes with, citing previous reports. EGCG appears most likely to inhibits the early stage of infections, such as attachment, entry, and membrane fusion, by interfering with viral membrane proteins. According to the relationships between structure and antiviral activity of catechin derivatives, the 3-galloyl and 5'-OH group of catechin derivatives appear critical to antiviral activities. Enhancing the binding affinity of EGCG to virus particles would thus be important to increase virucidal activity. We propose a newly developed EGCG-fatty acid derivative in which the fatty acid on the phenolic hydroxyl group would be expected to increase viral and cellular membrane permeability. EGCG-fatty acid monoesters showed improved antiviral activities against different types of viruses, probably due to their increased affinity for virus and cellular membranes. Our study promotes the application of EGCG-fatty acid derivatives for the prevention and treatment of viral infections.

Keywords: attachment; budding; catechin; entry; epigallocatechin-3-O-gallate; fatty acid derivative; fusion; replication; virus inhibition.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of natural catechins. (−)-epigallocatechin-3-O-gallate (EGCG; 1), (+)-gallocatechin-3-O-gallate ((+)-GCG; 2), (-)-gallocatechin-3-O-gallate ((−)-GCG; 3), 5,7-dideoxy-EGCG (DO-EGCG; 4), epigallocatechin 3,5-digallate (EGCDG; 5), EGCG-thioether derivatives (6), EGCG-n-octadecylisocyanate derivative (7), EGCG-fatty acid monoester derivatives (8), EGCG-fatty acid tetra, octaester derivatives (9), (−)-epicatechin-3-O-gallate (ECG; 10), (−)-catechin-3-O-gallate (CG; 11), (−)-epigallocatechin (EGC; 12), (−)-gallocatechin (GC; 13), delphinidin (14), (−)-epicatechin (EC; 15), (−)-catechin (C; 16), 2′,2′-bisepigallocatechin digallate (bEGCdG; 17), rhodisin (18), theasinensin A (19), P2 (20), epicatechin-3-O-gallate-(4β→8)-epicatechin-3-O-gallate (21), procyanidin B2 (22), theaflavin (TF; 23) theaflavin-3-gallate (TF-3-G; 24), theaflavin-3′-gallate (TF-3′-G; 25), and theaflavin-3,3′-O-digallate (TFDG; 26).
Figure 1
Figure 1
Chemical structures of natural catechins. (−)-epigallocatechin-3-O-gallate (EGCG; 1), (+)-gallocatechin-3-O-gallate ((+)-GCG; 2), (-)-gallocatechin-3-O-gallate ((−)-GCG; 3), 5,7-dideoxy-EGCG (DO-EGCG; 4), epigallocatechin 3,5-digallate (EGCDG; 5), EGCG-thioether derivatives (6), EGCG-n-octadecylisocyanate derivative (7), EGCG-fatty acid monoester derivatives (8), EGCG-fatty acid tetra, octaester derivatives (9), (−)-epicatechin-3-O-gallate (ECG; 10), (−)-catechin-3-O-gallate (CG; 11), (−)-epigallocatechin (EGC; 12), (−)-gallocatechin (GC; 13), delphinidin (14), (−)-epicatechin (EC; 15), (−)-catechin (C; 16), 2′,2′-bisepigallocatechin digallate (bEGCdG; 17), rhodisin (18), theasinensin A (19), P2 (20), epicatechin-3-O-gallate-(4β→8)-epicatechin-3-O-gallate (21), procyanidin B2 (22), theaflavin (TF; 23) theaflavin-3-gallate (TF-3-G; 24), theaflavin-3′-gallate (TF-3′-G; 25), and theaflavin-3,3′-O-digallate (TFDG; 26).
Figure 2
Figure 2
The DNA and RNA viruses described in this study were classified by Baltimore group. A representative of each virus family and their structures are summarized in the figures. (A) Herpes simplex virus-1 is a member of Herpesviridae, classified to Baltimore group I possessing dsDNA as the genome in a nucleocapsid core enveloped by lipid membrane. (B) Hepatitis C virus and (C) Dengue virus are member of Flaviviridae, classified to Baltimore group IV possessing a (+) single-stranded RNA genome in the viral particle. (D) Influenza A virus is a member of Orthomyxoviridae, classified to Baltimore group V possessing eight (−)-strand viral RNA genomes in the viral particle. (E) Human immunodeficiency virus-1 is a member of Retroviridae, classified to Baltimore VI possessing two (+)-strand RNA genomes in a protein core in the viral particle.
Figure 3
Figure 3
Schematic overviews of the virus life cycles of (1) HSV, (2) HCV, (3) IAV, and (4) HIV-1 in infected cells. Their infection processes were divided by five steps. Step A: virus attaches to cell surface receptor. Step B: virus entry into cells by endocytosis. Step C: virus-cell membrane fusion. Step D: viral genome replication and synthesis of progeny viral components. Step E: budding of newly developed progeny virions.

References

    1. Wang Y., Ho C.-T. Polyphenolic Chemistry of Tea and Coffee: A Century of Progress. J. Agric. Food Chem. 2009;57:8109–8114. doi: 10.1021/jf804025c.
    1. Nakayama M., Suzuki K., Toda M., Okubo S., Hara Y., Shimamura T. Inhibition of the infectivity of influenza virus by tea polyphenols. Antivir. Res. 1993;21:289–299. doi: 10.1016/0166-3542(93)90008-7.
    1. Taguri T., Tanaka T., Kouno I. Antibacterial spectrum of plant polyphenols and extracts depending upon hydroxyphenyl structure. Biol. Pharm. Bull. 2006;29:2226–2235. doi: 10.1248/bpb.29.2226.
    1. Chen D., Daniel K.G., Kuhn D.J., Kazi A., Bhuiyan M., Li L., Wang Z., Wan S.B., Lam W.H., Chan T.H., et al. Green tea and tea polyphenols in cancer prevention. Front. Biosci. 2004;9:2618–2631. doi: 10.2741/1421.
    1. Lyu S.-Y., Rhim J.-Y., Park W.-B. Antiherpetic Activities of Flavonoids against Herpes Simplex Virus Type 1 (HSV-1) and Type 2 (HSV-2) In Vitro. Arch. Pharm. Res. 2005;28:1293–1301. doi: 10.1007/BF02978215.
    1. Savi L.A., Barardi C.R.A., Simoes C.M.O. Evaluation of Antiherpetic Activity and Genotoxic Effects of Tea Catechin Derivatives. J. Agric. Food Chem. 2006;54:2552–2557. doi: 10.1021/jf052940e.
    1. Isaacs C.E., Wen G.Y., Xu W., Jia J.H., Rohan L., Corbo C., Di Maggio V., Jenkins E.C., Jr., Hillier S. Epigallocatechin Gallate Inactivates Clinical Isolates of Herpes Simplex Virus. Antimicrob. Agents Chemother. 2008;52:962–970. doi: 10.1128/AAC.00825-07.
    1. Gescher K., Hensel A., Hafezi W., Derksen A., Kuhn J. Oligomeric proanthocyanidins from Rumex acetosa L. inhibit the attachment of herpes simplex virus type-1. Antivir. Res. 2011;89:9–18. doi: 10.1016/j.antiviral.2010.10.007.
    1. Isaacs C.E., Xu W., Merz G., Hillier S., Rohan L., Wen G.Y. Digallate Dimers of (−)-Epigallocatechin Gallate Inactivate Herpes Simplex Virus. Antimicrob. Agents Chemother. 2011;55:5646–5653. doi: 10.1128/AAC.05531-11.
    1. Colpitts C.C., Schang L.M. A Small Molecule Inhibits Virion Attachment to Heparan Sulfate- or Sialic Acid-Containing Glycans. J. Virol. 2014;88:7806–7817. doi: 10.1128/JVI.00896-14.
    1. Pradhan P., Nguyen M.L. Herpes simplex virus virucidal activity of MST-312 and epigallocatechin gallate. Virus Res. 2018;249:93–98. doi: 10.1016/j.virusres.2018.03.015.
    1. Weber J.M., Ruzindana-Umunyana A., Imbeault L., Sircar S. Inhibition of adenovirus infection and adenain by green tea catechins. Antivir. Res. 2003;58:167–173. doi: 10.1016/S0166-3542(02)00212-7.
    1. He L., Zhang E., Shi J., Li X., Zhou K., Zhang Q., Le A.D., Tang X. (−)-Epigallocatechin-3-gallate inhibits human papillomavirus (HPV)-16 oncoprotein-induced angiogenesis in non-small cell lung cancer cells by targeting HIF-1a. Cancer Chemother. Pharmacol. 2013;71:713–725. doi: 10.1007/s00280-012-2063-z.
    1. He W., Li L.-X., Liao Q.-J., Liu C.-L., Chen X.-L. Epigallocatechin gallate inhibits HBV DNA synthesis in a viral replication-inducible cell line. World J. Gastroenterol. 2011;17:1507–1514. doi: 10.3748/wjg.v17.i11.1507.
    1. Zuo G., Li Z., Chen L., Xu X. Activity of compounds from Chinese herbal medicine Rhodiola kirilowii (Regel) Maxim against HCV NS3 serine protease. Antivir. Res. 2007;76:86–92. doi: 10.1016/j.antiviral.2007.06.001.
    1. Ciesek S., von Hahn T., Colpitts C.C., Schang L.M., Friesland M., Steinmann J., Manns M.P., Ott M., Wedemeyer H., Meuleman P., et al. The Green Tea Polyphenol, Epigallocatechin-3-Gallate, Inhibits Hepatitis C Virus Entry. Hepatology. 2011;54:1947–1955. doi: 10.1002/hep.24610.
    1. Calland N., Albecka A., Belouzard S., Wychowski C., Duverlie G., Descamps V., Hober D., Dubuisson J., Rouillé Y., Séron K. (−)-Epigallocatechin-3-Gallate Is a New Inhibitor of Hepatitis C Virus Entry. Hepatology. 2012;55:720–729. doi: 10.1002/hep.24803.
    1. Bhat R., Adam A.T., Lee J.J., Deloison G., Rouillé Y., Séron K., Rotella D.P. Structure-activity studies of (−)-epigallocatechin gallate derivatives as HCV entry inhibitors. Bioorg. Med. Chem. Lett. 2014;24:4162–4165. doi: 10.1016/j.bmcl.2014.07.051.
    1. Calland N., Sahuc M.E., Belouzard S., Pène V., Bonnafous P., Mesalam A.A., Deloison G., Descamps V., Sahpaz S., Wychowski C., et al. Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action. J. Virol. 2015;89:10053–10063. doi: 10.1128/JVI.01473-15.
    1. Carneiro B.M., Batista M.N., Braga A.C.S., Nogueira M.L., Rahal P. The green tea molecule EGCG inhibits Zika virus entry. Virology. 2016;496:215–218. doi: 10.1016/j.virol.2016.06.012.
    1. Gupta D., Pathan J.K., Malviya S., Kharia A. The recent allopathic and herbal approaches for Zika Virus. Int. J. Pharm. Life Sci. 2016;7:5271–5280.
    1. Sharma N., Murali A., Singh S.K., Giri R. Epigallocatechin gallate, an active green tea compound inhibits the Zika virus entry into host cells via binding the envelope protein. Int. J. Biol. Macromol. 2017;104:1046–1054. doi: 10.1016/j.ijbiomac.2017.06.105.
    1. Vázquez-Calvo Á., Jiménez de Oya N., Martín-Acebes M.A., Garcia-Moruno E., Saiz J.C. Antiviral Properties of the Natural Polyphenols Delphinidin and Epigallocatechin Gallate against the Flaviviruses West Nile Virus, Zika Virus, and Dengue Virus. Front. Microbiol. 2017;8:1314. doi: 10.3389/fmicb.2017.01314.
    1. Raekiansyah M., Buerano C.C., Luz M.A.D., Morita K. Inhibitory effect of the green tea molecule EGCG against dengue virus infection. Arch. Virol. 2018;163:1649–1655. doi: 10.1007/s00705-018-3769-y.
    1. Lu J.-W., Hsieh P.-S., Lin C.-C., Hu M.-K., Huang S.-M., Wang Y.-M., Liang C.-Y., Gong Z., Ho Y.-J. Synergistic effects of combination treatment using EGCG and suramin against the chikungunya virus. Biochem. Biophys. Res. Commun. 2017;491:595–602. doi: 10.1016/j.bbrc.2017.07.157.
    1. Zhao C., Liu S., Li C., Yang L., Zu Y. In Vitro Evaluation of the Antiviral Activity of the Synthetic Epigallocatechin Gallate Analog-Epigallocatechin Gallate (EGCG) Palmitate against Porcine Reproductive and Respiratory Syndrome Virus. Viruses. 2014;6:938–950. doi: 10.3390/v6020938.
    1. Chang C.W., Hsu F.L., Lin J.Y. Inhibitory Effects of Polyphenolic Catechins from Chinese Green Tea on HIV Reverse Transcriptase Activity. J. Biomed. Sci. 1994;1:163–166. doi: 10.1007/BF02253344.
    1. Tillekeratne L.M.V., Sherette A., Grossman P., Hupe L., Hupe D., Hudson R.A. Simplified Catechin-Gallate Inhibitors of HIV-1 Reverse Transcriptase. Bioorg. Med. Chem. Lett. 2001;11:2763–2767. doi: 10.1016/S0960-894X(01)00577-7.
    1. Kawai K., Tsuno N.H., Kitayama J., Okaji Y., Yazawa K., Asakage M., Hori N., Watanabe T., Takahashi K., Nagawa H. Epigallocatechin gallate, the main component of tea polyphenol, binds to CD4 and interferes with gp120 binding. J. Allergy Clin. Immunol. 2003;112:951–957. doi: 10.1016/S0091-6749(03)02007-4.
    1. Liu S., Lu H., Zhao Q., He Y., Niu J., Debnath A.K., Wu S., Jiang S. 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. doi: 10.1016/j.bbagen.2005.02.012.
    1. Williamson M.P., McCormick T.G., Nance C.L., Shearer W.T. Epigallocatechin gallate, the main polyphenol in green tea, binds to the T-cell receptor, CD4: Potential for HIV-1 therapy. J. Allergy Clin. Immunol. 2006;118:1369–1374. doi: 10.1016/j.jaci.2006.08.016.
    1. Nance C.L., Siwak E.B., Shearer W.T. Preclinical development of the green tea catechin, epigallocatechin gallate, as an HIV-1 therapy. J. Allergy Clin. Immunol. 2009;123:459–465. doi: 10.1016/j.jaci.2008.12.024.
    1. Jiang F., Chen W., Yi K., Wu Z., Si Y., Han W., Zhao Y. The evaluation of catechins that contain a galloyl moiety as potential HIV-1 integrase inhibitors. Clin. Immunol. 2010;137:347–356. doi: 10.1016/j.clim.2010.08.007.
    1. Li S., Hattori T., Kodama E.N. Epigallocatechin gallate inhibits the HIV reverse transcription step. Antivir. Chem. Chemother. 2011;21:239–243. doi: 10.3851/IMP1774.
    1. Hartjen P., Frerk S., Hauber I., Matzat V., Thomssen A., Holstermann B., Hohenberg H., Schulze W., Schulze zur Wiesch J., van Lunzen J. Assessment of the range of the HIV-1 infectivity enhancing effect of individual human semen specimen and the range of inhibition by EGCG. AIDS Res. Ther. 2012;9:2–9. doi: 10.1186/1742-6405-9-2.
    1. Castellano L.M., Hammond R.M., Holmes V.M., Weissman D., Shorter J. Epigallocatechin-3-gallate rapidly remodels PAP85-120, SEM1(45-107), and SEM2(49-107) seminal amyloid fibrils. Biol. Open. 2015;4:1206–1212. doi: 10.1242/bio.010215.
    1. Reid S.P., Shurtleff A.C., Costantino J.A., Tritsch S.R., Retterer C., Spurgers K.B., Bavari S. HSPA5 is an essential host factor for Ebola virus infection. Antivir. Res. 2014;109:171–174. doi: 10.1016/j.antiviral.2014.07.004.
    1. Green R.H. Inhibition of multiplication of influenza virus by extracts of tea. Proc. Soc. Exp. Biol. Med. 1949;71:84–85. doi: 10.3181/00379727-71-17089P.
    1. Imanishi N., Tuji Y., Katada Y., Maruhashi M., Konosu S., Mantani N., Terasawa K., Ochiai H. Additional Inhibitory Effect of Tea Extract on the Growth of Influenza A and B Viruses in MDCK Cells. Microbiol. Immunol. 2002;46:491–494. doi: 10.1111/j.1348-0421.2002.tb02724.x.
    1. Song J.-M., Lee K.-H., Seong B.-L. Antiviral effect of catechins in green tea on influenza virus. Antivir. Res. 2005;68:66–74. doi: 10.1016/j.antiviral.2005.06.010.
    1. Furuta T., Hirooka Y., Abe A., Sugata Y., Ueda M., Murakami K., Suzuki T., Tanaka K., Kan T. Concise synthesis of dideoxy-epigallocatechin gallate (DO-EGCG) and evaluation of its anti-influenza virus activity. Bioorg. Med. Chem. Lett. 2007;17:3095–3098. doi: 10.1016/j.bmcl.2007.03.041.
    1. Kuzuhara T., Iwai Y., Takahashi H., Hatakeyama D., Echigo N. Green tea catechins inhibit the endonuclease activity of influenza A virus RNA polymerase. PLoS Curr. 2009;1:RRN1052. doi: 10.1371/currents.RRN1052.
    1. Zu M., Yang F., Zhou W., Liu A., Du G., Zheng L. In vitro anti-influenza virus and anti-inflammatory activities of theaflavin derivatives. Antivir. Res. 2012;94:217–224. doi: 10.1016/j.antiviral.2012.04.001.
    1. Ling J.-X., Wei F., Li N., Li J.-L., Chen L.-J., Liu Y.-Y., Luo F., Xiong H.-R., Hou W., Yang Z.-Q. Amelioration of influenza virus-induced reactive oxygen species formation by epigallocatechin gallate derived from green tea. Acta Pharmacol. Sin. 2012;33:1533–1541. doi: 10.1038/aps.2012.80.
    1. Kowalinski E., Zubieta C., Wolkerstorfer A., Szolar O.H.J., Ruigrok R.W.H., Cusack S. Structural Analysis of Specific Metal Chelating Inhibitor Binding to the Endonuclease Domain of Influenza pH1N1 (2009) Polymerase. PLoS Pathog. 2012;8:e1002831. doi: 10.1371/journal.ppat.1002831.
    1. Kim M., Kim S.-Y., Lee H.W., Shin J.S., Kim P., Jung Y.-S., Jeong H.-S., Hyun J.-K., Lee C.-K. Inhibition of influenza virus internalization by (−)-epigallocatechin-3-gallate. Antivir. Res. 2013;100:460–472. doi: 10.1016/j.antiviral.2013.08.002.
    1. Müller P., Downard K.M. Catechin inhibition of influenza neuraminidase and its molecular basis with mass spectrometry. J. Pharm. Biomed. Anal. 2015;111:222–230. doi: 10.1016/j.jpba.2015.03.014.
    1. Quosdorf S., Schuetz A., Kolodziej H. Different Inhibitory Potencies of Oseltamivir Carboxylate, Zanamivir, and Several Tannins on Bacterial and Viral Neuraminidases as Assessed in a Cell-Free Fluorescence-Based Enzyme Inhibition Assay. Molecules. 2017;22:1989. doi: 10.3390/molecules22111989.
    1. Tanaka T., Kusano R., Kouno I. Synthesis and antioxidant activity of novel amphipathic derivatives of tea polyphenol. Bioorg. Med. Chem. Lett. 1998;8:1801–1806. doi: 10.1016/S0960-894X(98)00311-4.
    1. Mori S., Miyake S., Kobe T., Nakaya T., Fuller S.D., Kato N., Kaihatsu K. Enhanced anti-influenza A virus activity of (−)-epigallocatechin-3-O-gallate fatty acid monoester derivatives: Effect of alkyl chain length. Bioorg. Med. Chem. Lett. 2008;18:4249–4252. doi: 10.1016/j.bmcl.2008.02.020.
    1. Wu X.L., He W.Y., Yao L., Zhang H.P., Liu Z.G., Wang W.P., Ye Y., Cao J.J. Characterization of Binding Interactions of (−)-Epigallocatechin-3-gallate from Green Tea and Lipase. J. Agric. Food Chem. 2013;61:8829–8835. doi: 10.1021/jf401779z.
    1. Kaihatsu K., Mori S., Matsumura H., Daidoji T., Kawakami C., Kurata H., Nakaya T., Kato N. Broad and potent anti-influenza virus spectrum of epigallocatechin-3-O-gallate-monopalmitate. J. Mol. Genet. Med. 2009;3:195–197.
    1. Daidoji T., Kaihatsu K., Nakaya T. The Role of Apoptosis in Influenza Virus Pathogenesis and the Mechanisms Involved in Anti-Influenza Therapies. Curr. Chem. Biol. 2010;4:208–218.
    1. Kaihatsu K., Barnard D.L. Recent Developments in Anti-influenza A Virus Drugs and Use in Combination Therapies. Mini Rev. Org. Chem. 2012;9:3–10. doi: 10.2174/157019312799079965.
    1. Zhong Y., Ma C.-M., Shahidi F. Antioxidant and antiviral activities of lipophilic epigallocatechin gallate (EGCG) derivatives. J. Funct. Foods. 2012;4:87–93. doi: 10.1016/j.jff.2011.08.003.
    1. De Oliveira A., Adams S.D., Lee L.H., Murray S.R., Hsu S.D., Hammond J.R., Dickinson D., Chen P., Chu T.-C. Inhibition of herpes simplex virus type 1 with the modified green tea polyphenol palmitoyl-epigallocatechin gallate. Food Chem. Toxicol. 2013;52:207–215. doi: 10.1016/j.fct.2012.11.006.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi