The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan
Received Date: July 08, 2015; Accepted Date: July 09, 2015; Published Date: July 16, 2015
Citation: Kaihatsu K (2015) Potential Applications of Epigallocatechin Gallate-Fatty Acid Derivatives as Antiviral Agents. J Antivir Antiretrovir 7:lv-lvi. doi: 10.4172/jaa.1000e127
Copyright: © 2015 Kaihatsu K. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Epigallocatechin gallate; EGCG-fatty acid monoester; DNA virus; RNA virus; Membrane permeability; Chemical stability; Antiviral activity
EGCG: (-)-Epigallocatechin-3-O-gallate; MDCK: Madin-Darby Canine Kidney; HSV: Herpes Simplex Virus; HPV: Human Papilloma Virus; HBV: Hepatitis B Virus; HCV: Hepatitis C Virus; HIV-1: Human Immunodeficiency Virus-1; EGCG-C16: EGCG-Monopalmitate; EC50: 50% Effective Concentration
Epigallocatechin gallate (EGCG) (Figure 1a) is the major catechin component of green tea (Camellia sinensis). It has been shown to have antiviral properties against DNA viruses such as herpes simplex virus (HSV; Herpesviridae) , adenovirus (Adenoviridae) , human papilloma virus (HPV; Papovaviridae) , and hepatitis B virus (HBV; Hepadnaviridae) , and RNA viruses such as influenza virus (Orthomyxoviridae) , ebola virus (Firoviridae) , hepatitis C virus (HCV; Flaviviridae)  and human immunodeficiency virus-1 (HIV- 1; Retroviridae) .
The antiviral mechanisms of the actions of EGCG vary depending on its target virus. According to previous reports, EGCG directly interacts with the lipid membrane and the viral membrane proteins of influenza virus  and HCV  and interferes with viral entry or membrane fusion steps. ECGC has also been shown to inhibit late infection stages including reverse-transcription , transcription , integration [8,10], cell signal transduction  and protein chaperoning . Although these broad antiviral activities of EGCG are attractive, its poor chemical stability under physiological conditions  and low bioavailability (<0.3%) in vivo  are drawbacks preventing its use in its native form.
There have been several reports in which the chemical, biological and antiviral properties of EGCG were improved by chemical modification. Kouno et al. introduced an n-octadecyl group at the 4’-position of EGCG using isocyanate chemistry . They found that EGCG modified with a C18 alkyl group possesses increased hydrophobicity and lipid membrane affinity relative to natural EGCG. Mori et al. developed a method to introduce fatty acids into the B-ring or D-ring of EGCG using lipase-catalyzed transesterification . They found that the effectiveness of EGCG-fatty acid monoesters against influenza A/Puerto Rico/8/33 (H1N1) virus was increased in an alkyl chain length-dependent manner in Madin-Darby canine kidney (MDCK) cells . Among EGCG-saturated fatty acid monoesters, EGCG-monopalmitate (EGCG-C16) (Figure 1b) showed the highest anti-influenza virus activity . Although EGCG-C16 exhibited a slightly (3.2-fold) higher cytotoxic effect to MDCK cells, it showed significantly (23.5-fold) higher anti-influenza virus activity against the A/Puerto Rico/8/34(H1N1) strain . EGCG-C16 inhibited human-, swine- and avian-pathogenic influenza A viruses, and the EC50 was between 10 nM and 61 nM, a 7.1-fold to 44-fold lower concentration than unmodified EGCG . A lethal dose of avian-influenza A/H5N2 virus pretreated with EGCG-C16 completely prevented the death of embryonated chicken eggs inoculated with the virus by an allantoic cavity route .
Oliveira et al. reported that EGCG-C16 inhibited the adsorption step of herpes simplex virus infection in Vero cells . Zhao et al. reported that EGCG-C16 exhibits significantly higher antiviral activity against porcine reproductive and respiratory syndrome virus than natural EGCG and ribavirin as both pre-treatment and post-treatment . These reports suggest that the pronounced antiviral activities of EGCG-fatty acid derivatives were due to increased permeability through both the viral membrane and the cell membrane.
Although EGCG interferes with different types of viral infections, it is easily oxidized or hydrolyzed under physiological conditions because of the reactive hydroxyl groups in the gallyl moiety in the B-ring and the galloyl moiety in the D-ring [19,20]. However, addition of a palmitoyl group to the B-ring or D-ring prolonged its half-life in a cell culture medium approximately seven-fold .
These improved chemical, biological, and antiviral activities of this EGCG-fatty acid monoester should expand its application as an antiviral agent and may allow us to combat emerging drug-resistant viruses more effectively.