Abstract
Epigallocatechin gallate (EGCG) of green tea and the nutraceutical CystiCran®-40 (containing 40% proanthocyanidins) of the cranberry plant have been associated with antiviral activity. The purpose of this work was to determine the mechanism of antiviral synergy between each compound. Coliphage T4II (phage T4) and the rotavirus strain SA-11(RTV) were used as model virus systems. Individual and combined flavonoids structural and molecular weight analyses were performed by NMR and HPCL/MS, respectively. A suboptimal concentration of EGCG or C-40 alone or in combination reduced phage infectivity by ≤10%. Similarly, EGCG (30 µg/ml) and C-40 (25 µg/ml), respectively, reduced RTV titers by 3 and 13%. However, RTV titers were reduced by 32% (p < .05) with both flavonoids used in combination. RTV was not recognized in host cells by electron microscopy 24-h post-inoculation. NMR and HPLC/MS findings revealed significant structural and potential changes in molecular weight of the flavonoids in complex.
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References
Ahmad, A. L. M., & Tyrrell, D. A. J. (1986). Synergism between anti-rhinovirus antivirals: Various human interferons and a number of synthetic compounds. Antiviral Research, 6(4), 241–252.
Amoros, M., Simões, C. M., Girre, L., Sauvager, F., & Cormier, M. (1992). Synergistic effect of flavones and flavonols against herpes simplex virus type 1 in cell culture: Comparison with the antiviral activity of propolis. Journal of Natural Products, 55(12), 1732–1740.
Andrei, G., & Snoeck, R. (2013). Herpes simplex virus drug-resistance: New mutations and insights. Current Opinion in Infectious Diseases, 26(6), 551–560.
Ayisi, N. K., Gupta, S. V., & Babiuk, L. A. (1985). Combination chemotherapy: Interaction of 5-methoxymethyldeoxyuridine with trifluorothymidine, phosphonoformate and acycloguanosine against herpes simplex viruses. Antiviral Research, 5(1), 13–27.
Benelli, R., Venè, R., Bisacchi, D., Garbisa, S., & Albini, A. (2002). Anti-invasive effects of green tea polyphenol epigallocatechin-3-gallate (EGCG), a natural inhibitor of metallo and serine protease. Biological Chemistry, 383(3), 101–105.
Cabrera, C., Artacho, R., & Giménez, R. (2006). Beneficial effects of green tea—a review. Journal of the American College of Nutrigtion, 25(2), 79–99.
Carneiro, B. M., Batista, M. N., Braga, S., Nogueira, M. L., & Rahal, P. (2016). The green tea molecule EGCG inhibits Zika virus entry. Virology, 496, 215–218.
Carvalho, O. V., Botelho, C. V., Ferreira, C. G., Ferreira, H. C., Santos, M. R., Diaz, M. A., et al. (2013). In vitro inhibition of canine distemper virus by flavonoids and phenolic acids: Implications of structural differences for antiviral design. Research in Veterinary Science, 95(2), 717–724.
Cliver, D. (2009). Capsid and infectivity in virus detection. Food and Environmental Virology, 1, 123–128.
Collins, P. J., Haire, L. F., Lin, Y. P., Liu, J., Russell, R. J., Walker, P. A., et al. (2008). Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants. Nature, 453, 1258–1261.
Corcoran, M. P., McKay, D. L., & Blumberg, J. B. (2012). Flavonoid basics: Chemistry, sources, mechanisms of action, and safety. Journal of Nutrition, Gerontology, and Geriatrics, 31(3), 176–189.
Cuevas, J. M., Geller, R., Garijo, R., López-Aldeguer, J., & Sanjuán, R. (2015). Extremely high mutation rate of HIV-1 in vivo. PLoS Biology, 13(9), e1002251.
Cushnie, T. P. T., & Lamb, A. J. (2005). Antimicrobial activity of flavonoids. International Journal of Antimicrobial Agents, 26(5), 343–356.
de Lourdes Mata-Bilbao, M., Ristiona Andres-Laciueva, C., Roura, E., Jauregui, O., Torre, C., & Maria Lamuela-Raventos, R. (2007). A new LC/MS/MS rapid and sensitive method for the determination of green tea catechins and their metabolites in biological samples. Agricultural and Food Chemistry, 55(22), 8857–8863.
Du, G.-J., Zhang, Z., Wen, X.-D., Yu, C., Calway, T., Yuan, C.-S., et al. (2012). Epigallocatechin gallate (EGCG) is the most effective cancer chemopreventive polyphenol in green tea. Nutrients, 4(11), 1679–1691.
Gescher, K., Hensel, A., Hafezi, W., Derksen, A., & Kuhn, J. (2011). Oligomeric proanthocyanidins from Rumex acetosa L. inhibit the attachment of herpes simplex virus type-1. Antiviral Research, 89(1), 9–18.
Hagerman, A. E., & Butler, L. G. (1981). The specificity of proanthocyanidin-protein interactions. Journal of Biological Chemistry, 56(9), 4494–4497.
Hakki, M., & Chou, S. (2011). The biology of cytomegalovirus drug resistance. Current Opinion in Infectious Diseases, 24(6), 605–611.
Ho, H. Y., Cheng, M. L., Weng, S. F., Leu, Y. L., & Chiu, D. T. (2009). Antiviral effect of epigallocatechin gallate on enterovirus 71. Journal of Agricultural and Food Chemistry, 57(14), 6140–6147.
Hübner, W., McNerney, G. P., Chen, P., Dale, B. M., Gordon, R. E., Chuang, F. Y., et al. (2009). Quantitative 3D video microscopy of HIV transfer across T cell virological synapses. Science, 323(5922), 1743–1747.
Isaacs, C. E., Guang, Y. W., Xu, W., Jia, J. H., Rohan, L., Corbo, C., et al. (2008). Epigallocatechin gallate inactivates clinical isolates of herpes simplex virus. Antimicrobial Agents and Chemotherapy, 52(3), 962–970.
Isaacs, C. E., Xu, W., Merz, G., Hillier, S., Rohan, L., & Wen, G. Y. (2011). Digallate dimers of (−)-epigallocatechin gallate inactivate herpes simplex virus. Antimicrobial Agents and Chemotherapy, 55(12), 5646–5653.
Ji, H.-F., Li, X. J., & Zhang, H.-Y. (2009). Natural products and drug discovery. Can thousands of years of ancient medical knowledge lead us to new and powerful drug combinations in the fight against cancer and dementia? EMBO Reports, 10(3), 194–200.
Kassaye, S. G., Grossman, Z., Balamane, M., Johnston-White, B., Liu, C., Kumar, P., et al. (2016). Transmitted HIV drug resistance high and longstanding in metropolitan Washington, DC. Clinical Infectious Disease, 63(6), 836–843.
Kawai, K., Tsuno, N. H., Kitayama, J., Okaji, Y., Yazawa, K., Asakage, M., et al. (2003). Epigallocatechin gallate, the main component of tea polyphenol, binds to CD4 and interferes with gp120 binding. Journal of Allergy and Clinical Immunology, 112(5), 951–957.
Kruger, M. J., Davies, N., Myburgh, K. H., & Lecour, S. (2014). Proanthocyanidins, anthocyanins and cardiovascular disease. Food Research International, 59, 41–52.
Legeay, S., Rodier, M., Fillon, L., Faure, S., & Clere, N. (2015). Review epigallocatechin gallate: A review of its beneficial properties to prevent metabolic syndrome. Nutrients, 7(7), 5443–5468.
Li, S., Hattori, T., & Kodama, E. N. (2011). Epigallocatechin gallate inhibits the HIV reverse transcription step. Antiviral Chemistry & Chemotherapy, 21(6), 239–243.
Lipson, S. M., & Alsmadi, O. (1989). Enhancement of bacteriophage φX-174 plaques by homoionic clay minerals. Journal of General Microbiology, 135, 3497–3503.
Lipson, S. M., Gordon, R. E., Karthekeyan, L., Singh, M., Burdowski, A., Roy, M., et al. (2010). Effect of cranberry and grape juice drinks on enteric virus Integrity, infectivity in cell culture, and pathology in the animal model. In M. Qian & A. Rimando (Eds.), Flavor and health benefits of small fruits (pp. 177–195). Chicago, IL: American Chemistry Society Press.
Lipson, S. M., Ozen, F. S., Karthikeyan, L., Bulut, O., Hyka, X., Sullivan, G. L., et al. (2013). Flavonoid-associated direct loss of rotavirus antigen/antigen activity in cell-free suspension. Journal of Medicinally Active Plants, 2(1), 10–24.
Lipson, S. M., Ozen, F. S., Louis, S., & Karthikeyan, L. (2015). Comparison of α-glucosyl hesperidin and epigallocatechin gallate on the loss of rotavirus infectivity in host cell cultures. Frontiers in Microbiology, 6, 359. doi:10.3389/fmicb.2015.00359.
Liu, R. H. (2013). Dietary bioactive compounds and their health implications. Journal of Food Science, 78(s1), A18–A25.
Martin, M. M., Rockholm, D. C., & Martin, J. S. (1985). Effects of surfactants, pH, certain cations on precipitation of proteins by tannins. Journal of Chemical Ecology, 11(4), 485–495.
Meng, Z.-D., Birch, C., Heath, R., & Gust, I. (1987). Physicochemical stability and inactivation of human and simian rotaviruses. Applied and Environmental Microbiology, 53(4), 727–730.
Nagai, T., Miyaichi, Y., Tomimori, T., Suzuki, Y., & Yamaha, H. (1992). Antiviral activity of two flavonoids from Tanacetum microphyllum. Antiviral Research, 19(3), 207–216.
Orhan, D. D., Özçelik, B., Özgen, S., & Ergun, F. (2010). Antibacterial, antifungal, and antiviral activities of some flavonoids. Microbiology Research, 165(6), 496–504.
Razonable, R. R. (2011). Antiviral drugs for viruses other than human immunodeficiency virus. Mayo Clinic Proceedings, 86(10), 1009–1026.
Reed, L. J., & Muench, H. (1938). A simple method of estimating fifty percent endpoints. American Journal of Hygiene, 27, 493–497.
Rendeiro, C., Rhodes, J. S., & Spencer, J. P. E. (2015). The mechanisms of action of flavonoids in the brain: Direct versus indirect effects. Neurochemistry International, 89, 126–139.
Reygaert, W. C. (2014). The antimicrobial possibilities of green tea. Frontiers in Microbiology, 5, 434.
Ross, M., Rosato, V., Bosetti, C., Lagiou, P., Parpinel, M., Bertuccio, P., et al. (2010). Flavonoids, proanthocyanidins, and the risk of stomach cancer. Cancer Causes and Control, 21(10), 1597–1604.
Rubin, L. G. Pediatric infectious diseases. Personal Communication. Department of Pediatrics, Northwell Health Physician Partners, New Hyde Park, NY.
Song, J. M., Lee, K. H., & Seong, B. L. (1995). Antiviral effect of catechins in green tea on influenza virus. Antiviral Research, 68(2), 66–74.
Steinmann, J., Buer, J., Pietschmann, T., & Steinmann, E. (2013). Anti-infective properties of epigallocatechin-3-gallate (EGCG), a component of green tea. British Journal of Pharmacology, 168(5), 1059–1073.
Tapas, A., Sakarkar, D. M., & Kakde, R. B. (2008). Flavonoids as nutraceuticals: A review. Tropical Journal of Pharmacology Research, 7(3), 1089–1099.
Tomasevich, L. L., & Collum, D. B. (2014). Method of continuous variation: Characterization of alkali metal enolates using 1H and 19F NMR spectroscopies. Journal of the American Chemical Society, 136(27), 9710–9718.
Tortora, G. J., Funke, B. R., & Case, C. L. (2013). Microbiology. An introduction (11th edn, pp. 579–585). New York: Pearson Education Press.
Vlietinck, A. J., De Bruyne, T., Apers, S., & Pieters, L. A. (1998). Plant derived leading compounds for chemotherapy of human immunodeficiency virus (HIV) infection. Planta Medicine, 64, 97–109.
Weber, J. M., Ruzindana-Umunyana, A., Imbeault, L., & Sircar, S. (2003). Inhibition of adenovirus infection and adenain by green tea catechins. Antiviral Research, 58(2), 167–173.
Zhang, T., Zhiqiang, W., Du, J., Hu, Y., Liu, L., Yang, F., et al. (2012). Anti-Japanese-encephalitis-viral effects of kaempferol and Daidzin and their RNA-binding characteristics. PLoS ONE, 7(1), e30259. doi:10.1371/journal.pone.0030259.
Zhong, L., Hu, J., Shu, W., Gao, B., & Xiong, S. (2015). Epigallocatechin-3-gallate opposes HBV-induced incomplete autophagy by enhancing lysosomal acidification, which is unfavorable for HBV replication. Cell Death and Disease, 6, e1770. doi:10.1038/cddis.2015.136.
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This work was supported by Grants from the St. Francis College Faculty Research Committee and by special research funds from the New York City College of Technology of the City University of New York. The authors wish to thank Heleen P. Lipson, M.S.E., for proofreading the manuscript.
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Lipson, S.M., Karalis, G., Karthikeyan, L. et al. Mechanism of Anti-rotavirus Synergistic Activity by Epigallocatechin Gallate and a Proanthocyanidin-Containing Nutraceutical. Food Environ Virol 9, 434–443 (2017). https://doi.org/10.1007/s12560-017-9299-z
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DOI: https://doi.org/10.1007/s12560-017-9299-z