Antiviral Mechanism of Action of Epigallocatechin-3-O-gallate and Its Fatty Acid Esters
Abstract
:1. Introduction
2. Classifications, Structures, and Life Cycles of Viruses Discussed in This Review
2.1. Herpes Simplex Virus (HSV)
2.2. Hepatitis C Virus (HCV), Zika Virus (ZIKV), West Nile Virus (WNV), Dengue Virus (DENV), and Chikungunya Virus (CHIKV)
2.3. Influenza A Virus (IAV)
2.4. Human Immunodeficiency Virus-1 (HIV-1)
3. Antiviral Activity of Catechins on Enveloped DNA Viruses
4. Antiviral Activity of Catechins on Enveloped (+) ssRNA Viruses
5. Antiviral Activity of Catechins on Enveloped (−) RNA Virus
5.1. Antiviral Mechanism of Action of EGCG on HIV-1
5.2. Antiviral Mechanism of EGCG on Influenza Virus
6. Structure and Antiviral Activity of Catechin Derivatives
7. Lipid Bilayer Affinity of EGCG-Alkyl Ether Derivatives
8. EGCG-Fatty Acid Derivatives
8.1. Synthesis of EGCG-Fatty Acid Derivatives
8.2. Cytotoxicity and Influenza Virus Inhibitory Effect of EGCG and EGCG-Fatty Acid Derivatives
8.3. Anti-Influenza Virus Activity of EGCG-C16 in Chicken Embryonated Eggs
8.4. Antiviral Activity of EGCG-Fatty Acid Derivatives for Other Viruses
9. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AAPH | 2,2′-azobis(2-amidinopropane) dihydrocholoride |
AMVN | 2,2′-azobis (2,4-dimethylvaleronitrile) |
bEGCdG | 2′,2′-bisepigallocatechin digallate |
BVDV | bovine viral diarrhea virus |
C | (−)-catechin |
CC50 | 50% cytotoxic concentration |
CG | (−) catechin-3-O-gallate |
CHIKV | chikungunya virus |
DENV | dengue virus |
DO-EGCG | 5,7-dideoxy-EGCG |
E | envelope protein |
EBOV | Ebola virus |
EC | (−) epicatechin |
EC50 | 50% effective concentration |
ECG | (−) epicatechin-3-O-gallate |
EGC | (−)-epigallocatechin |
EGCDG | epigallocatechin 3,5-digallate |
EGCG | (−)-epigallocatechin-3-O-gallate |
ELISA | enzyme-linked immunosorbent assay |
EM | electron microscopy |
GC | (−)-gallocatechin |
GCG | gallocatechin-3-O-gallate |
HA | hemagglutinin |
HBV | hepatitis B virus |
HCV | hepatitis C virus |
HCVcc | cell-culture-derived HCV |
HPV | human papilloma virus |
HSV | herpes simplex virus |
HVEM | herpes virus entry mediator |
IAV | influenza A virus |
IC50 | 50% inhibitory concentration |
JEV | Japanese encephalitis |
M | matrix protein |
MALDI | matrix assisted laser desorption/ionization |
MDCK | Madin-Darby canine kidney |
MUNANA | 2′-(4-methylumbelliferyl)-α-d-N-acetylneuraminic acid |
NA | neuraminidase |
NS | nonstructural protein |
NMR | nuclear magnetic resonance |
PA | polymerase subunit A |
PB1 | polymerase subunit B1 |
PB2 | polymerase subunit B2 |
PRRSV | porcine reproductive and respiratory syndrome virus |
RNP | ribonucleoprotein |
RT | reverse transcription |
SINV | sindbis virus |
SEVI | semen-derived enhancer of virus infection |
TCID50 | 50% tissue culture infectious dose |
TF | theaflavin |
TFDG | theaflavin-3,3′-O-digallate |
TF-3-G | theaflavin-3-gallate |
TF-3′-G | theaflavin-3′-gallate |
WNV | West Nile viruses |
YFV | yellow fever virus |
ZIKV | zika virus |
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Compound | Virus | Assay | Activity | Ref. |
---|---|---|---|---|
ECG | HSV-1 F1/HSV-2 333 | Cytopathic effect inhibition | EC50 = 4.0/63.0 μM | [5] |
EC | EC50 = 2.5/35.0 μM | |||
EGC | HSV-1 KOS/HSV-1 29R | Virus replication inhibition | EC50 = 173.6/70.4 μM | [6] |
GC | EC50 = 103.3/140.1 μM | |||
C | EC50 = 630.0/629.4 μM | |||
EC | EC50 = 458.6/107.1 μM | |||
EGCG | HSV-1 F1/HSV-2 333 | Titer reduction | 102.0/104.4 reduction at 100 μM | [7,9] |
Theasinensin A | 104.0–5.0/104.0 reduction at 100 μM | |||
EGCG | HSV-1 17 syn+ | Cytotoxicity inhibition | 98% at 2.0 μM | [8] |
ECG | 36% at 2.0 μM | |||
EC | 16% at 2.0 μM | |||
GC | 3% at 2.0 μM | |||
EGCG | HSV-1 KOS | Plaque formation inhibition | 60% inhibition (2.0 μM at 4 °C) 98% inhibition (2.0 μM at RT) 80% inhibition (2.0 μM at 37 °C) | [11] |
Compound | Target | Assay | Activity | Ref. |
---|---|---|---|---|
EGCG | HCV serine protease (NS3-SP) | Serine protease inhibition | IC50 = 8.51 μM | [15] |
ECG | IC50 = 18.55 μM | |||
EGCG | HCVcc | Luciferase reporter | IC50 = 5.5 μM | [16] |
EGCG | HCVcc | Luciferase reporter | IC50 = 5.0 μM | [17] |
EGCG | ZIKV BR/ZIKV MR766 | Focus forming inhibition | >90% inhibition at 100 μM | [20] |
EGCG | WNV-NY99 | Plaque forming inhibition | >104.0 reduction at 10 μM | [23] |
ZIKV MR766 | >104.0 at 10 μM | |||
ZIKV PA259459 | >103.0 at 10 μM | |||
DENV-2 | >103.0 at 10 μM | |||
EGCG | CHIKV S27 | Microneutralization | IC50 = 1.99 μg/mL (4.34 μM) | [25] |
EGCG | DENV-1 | Antigen reduction | EC50 = 14.8 μM | [24] |
DENV-2 | EC50 = 18.0 μM | |||
DENV-3 | EC50 = 11.2 μM | |||
DENV-4 | EC50 = 13.6 μM |
Compound | Target | Assay | Activity | Ref. |
---|---|---|---|---|
EGCG | HIV-1 purified reverse transcriptase | Reverse transcriptase inhibition | IC50 = 0.68 μM | [27] |
ECG | IC50 = 0.32 μM | |||
EGC | IC50 = 7.80 μM | |||
EGCG | HIV-1 purified reverse transcriptase | Reverse transcriptase inhibition | IC50 = 0.73 μM | [28] |
ECG | IC50 = 0.76 μM | |||
EGCG | HIV-1 CD4 protein | Anti-CD4 binding to CD4 protein inhibition | Approx. 70% inhibition at 100 μM | [29] |
EGCG/GCG | HIV-1IIIB | p24 antigen production | IC50 = 9.89 μM/4.61 μM | [30] |
HIV-1IIIB | Cell-cell fusion | IC50 = no inhibition/7.55 μM | ||
HIV-1NL4-3-luc pseudotyped with HIV-1HXB2 | Virus-cell fusion | IC50 = 3.44 μM/2.45 μM | ||
EGCG | HIV-1 gp120 | Inhibition of gp120 binding to CD4+ cells | 40% inhibition at 0.2 μM | [31] |
EGCG | HIV-1SF162 (R5) | p24 antigen production | IC50 = 4.5 μM | [32] |
HIV-189.6 (X4/R5) | IC50 = 8.0 μM | |||
HIV-192UG038 (X4) | IC50 = 9.0 μM | |||
HIV-1JV1083 (R5) | IC50 = 9.0 μM | |||
EGCG/EGC | HIV-1 IIIB | Multinuclear activation of galactosidase inhibition | EC50 = 1.6 μM/3.4 μM | [34] |
HIV-2 EHO | EC50 = 2.0 μM/7.9 μM | |||
EGCG | HIV-1BAL(X5) | Semen-derived enhancer of virus infection monitored by luciferase reporter expression | Inhibited > 70.6% at 0.4 mM | [35] |
HIV-1NL4/3 (X4) | ||||
HIV-1B (isolate) | ||||
EGCG | HIV-1BL2 | Semen-derived enhancer of virus infection monitored by luciferase reporter expression | ~61% inhibition at 0.25 μM | [36] |
HIV-1BAL | ~35% inhibition at 0.25 μM | |||
HIV-89.6 | ~11% inhibition at 0.25 μM |
Compound | Target | Assay | Activity | Ref. |
---|---|---|---|---|
EGCG/ TFDG | A/Yamagata/120/86(H1N1) | Plaque forming inhibition | 100% inhibition at 1.5 μM/ 100% inhibition at 1.5 μM | [2] |
B/USSR/100/83 | 100% inhibition at 1.5 μM/ 100% inhibition at 1.5 μM | |||
EGCG/ ECG/EGC | A/Chile/1/83(H1N1) | Plaque forming inhibition | EC50 = 28.4/26.4/318 μM | [40] |
A/Sydney/5/97(H3N2) | EC50 = 22.8/22.2/309 μM | |||
B/Yamagata/16/88 | EC50 = 26.1/40.4/311.1 μM | |||
EGCG/ DO-EGCG | A/Memphis/1/71(H3N2) | Focus forming inhibition | IC50 = 41.25/11.92 μM | [41] |
EGCG/ ECG | N-terminal endonuclease domain protein of A/PR/8/34(H1N1) RNA polymerase PA | Endonuclease inhibition | 100% inhibition at 10 μM/ 100% inhibition at 10 μM | [42] |
TF, TF-3-G/ TF-3′-G/ TFDG | A/PR/8/34(H1N1) | NA inhibition | IC50 = 11.65 μg/mL (TF), IC50 = 31.91/35.23/26.25 μM | [43] |
A/Sydney/5/97(H3N2) | IC50 = 25.72 μg/mL (TF), IC50 = 13.29/18.26/10.67 μM | |||
B/Jiangsu/10/2003 | IC50 = 27.98 μg/mL (TF), IC50 = 49.60 /49.23 /42.07 μM | |||
EGCG | A/Yamagata/120/86(H1N1) | Lethal murine infection model | Survival rate improved from 16.7% to 66.7% at 40 mg·kg−1·d−1 oral administration | [44] |
EGCG | A/Puerto Rico/8/34 (H1N1) | NA activity inhibition | IC50 > 500 μM | [46] |
Purified NA from A/California/04/2009 (H275Y) | IC50 = 233.7 μM | |||
EGCG | A/PR/8/34(H1N1), A/USSR/90/77 (H1N1), A/Port Chalmers/1/73(H3N2), A/Aichi/2/68(H3N2) | Plaque forming inhibition | EC50 = 7.3~40.1 μM | [10] |
EGCG | A/California/04/2009(H1N1) | NA inhibition | IC50 =1565 μM | [48] |
(+)-GCG | IC50 = 396 μM |
Target Virus | Virus Inhibitory Effect | Important Functional Group | Targets | Ref. |
---|---|---|---|---|
HSV | EGC > EC, GC > C | 5′-OH | Entire infection process | [6] |
HCV | EGCG > ECG | 5′-OH | NS3-Serine Protease | [15] |
HIV-1 | ECG, EGCG > EGC | 3-galloyl | Reverse transcriptase | [27] |
HIV-1 | EGCG > EGC > ECG > C | 3-galloyl, 5′-OH | Glycoprotein(gp120) | [32] |
Influenza | EGCG > ECG > EGC | 3-galloyl | Hemagglutinin, viral RNA synthesis, Neuraminidase (NA) | [40] |
Influenza | EGCG > ECG > bEGCdG > EGC | 3-galloyl, 5′-OH | Viral envelope, NA surface glycoprotein | [46] |
Compound | Assay | CC50 [μM] | EC50 [μM] | SI |
---|---|---|---|---|
EGCG | Plaque formation reduction | 275.5 ± 6.00 μM | 94.6 ± 11.1 μM | 2.91 |
EGCG-C18 | 300.0 ± 25.0 μM | 64.0 ± 0.50 μM | 4.68 | |
EGCG-C18DE | 250.0 ± 25.0 μM | 7.00 ± 0.50 μM | 35.7 | |
EGCG-C18TE | 32.0 ± 3.50 μM | 3.00 ± 0.50 μM | 10.6 |
Compound | Assay | CC50 [μM] | EC50 [μM] | SI |
---|---|---|---|---|
EGCG | Plaque formation reduction | 275.5 ± 6.00 μM | 0.391 ± 0.056 μM | 703 |
EGCG-C18 | 300.0 ± 25.0 μM | 0.060 ± 0.010 μM | 5000 | |
EGCG-C18DE | 250.0 ± 25.0 μM | 0.180 ± 0.050 μM | 1389 | |
EGCG-C18TE | 32.0 ± 3.50 μM | 0.10 ± 0.208 μM | 320 |
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Kaihatsu, K.; Yamabe, M.; Ebara, Y. Antiviral Mechanism of Action of Epigallocatechin-3-O-gallate and Its Fatty Acid Esters. Molecules 2018, 23, 2475. https://doi.org/10.3390/molecules23102475
Kaihatsu K, Yamabe M, Ebara Y. Antiviral Mechanism of Action of Epigallocatechin-3-O-gallate and Its Fatty Acid Esters. Molecules. 2018; 23(10):2475. https://doi.org/10.3390/molecules23102475
Chicago/Turabian StyleKaihatsu, Kunihiro, Miyuki Yamabe, and Yasuhito Ebara. 2018. "Antiviral Mechanism of Action of Epigallocatechin-3-O-gallate and Its Fatty Acid Esters" Molecules 23, no. 10: 2475. https://doi.org/10.3390/molecules23102475