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

Chen, Chao; Qiu, Hui; Gong, Jianping; Liu, Qing; Xiao, Han; Chen, Xinwen; Sun, Binlian; Yang, Rongge

doi:10.1007/s00705-012-1304-0

Cited by 92 publications

(67 citation statements)

References 60 publications

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“…This natural compound belongs to the flavonoid family, like the catechin EGCG identified by us and others as a new anti-HCV agent (7)(8)(9). Our results show that the hydroxyl groups at R3=, R5=, and R3 are important in conferring antiviral activity on delphinidin, whereas a free hydroxyl group at R3 is not required in the case of EGCG (7).…”

Section: Discussionmentioning

confidence: 57%

Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action

Calland

Sahuc

Belouzard

et al. 2015

J Virol

122

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Despite the validation of direct-acting antivirals for hepatitis C treatment, the discovery of new compounds with different modes of action may still be of importance for the treatment of special patient populations. We recently identified a natural molecule, epigallocatechin-3-gallate (EGCG), as an inhibitor of hepatitis C virus (HCV) targeting the viral particle. The aim of this work was to discover new natural compounds with higher anti-HCV activity than that of EGCG and determine their mode of action. Eight natural molecules with structure similarity to EGCG were selected. HCV JFH1 in cell culture and HCV pseudoparticle systems were used to determine the antiviral activity and mechanism of action of the compounds. We identified delphinidin, a polyphenol belonging to the anthocyanidin family, as a new inhibitor of HCV entry. Delphinidin inhibits HCV entry in a pangenotypic manner by acting directly on the viral particle and impairing its attachment to the cell surface. Importantly, it is also active against HCV in primary human hepatocytes, with no apparent cytotoxicity and in combination with interferon and boceprevir in cell culture. Different approaches showed that neither aggregation nor destruction of the particle occurred. Cryo-transmission electron microscopy observations of HCV pseudoparticles treated with delphinidin or EGCG showed a bulge on particles that was not observed under control conditions. In conclusion, EGCG and delphinidin inhibit HCV entry by a new mechanism, i.e., alteration of the viral particle structure that impairs its attachment to the cell surface. IMPORTANCEIn this article, we identify a new inhibitor of hepatitis C virus (HCV) infection, delphinidin, that prevents HCV entry. This natural compound, a plant pigment responsible for the blue-purple color of flowers and berries, belongs to the flavonoid family, like the catechin EGCG, the major component present in green tea extract, which is also an inhibitor of HCV entry. We studied the mode of action of these two compounds against HCV and demonstrated that they both act directly on the virus, inducing a bulging of the viral envelope. This deformation might be responsible for the observed inhibition of virus attachment to the cell surface. The discovery of such HCV inhibitors with an unusual mode of action is important to better characterize the mechanism of HCV entry into hepatocytes and to help develop a new class of HCV entry inhibitors. H epatitis C is a major health problem, with as many as 130 million people chronically infected worldwide (1). It is caused by hepatitis C virus (HCV), which has a high propensity to establish a persistent infection. Chronic hepatitis C can lead to the development of cirrhosis and hepatocellular carcinoma. Recent improvements in the standard of care, with direct-acting antivirals (DAAs) that inhibit HCV NS3/4A protease, NS5B polymerase, or NS5A, and now without interferon (IFN), which causes severe adverse effects, have raised the hope that HCV infection can be managed efficiently in cou...

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Section: Discussionmentioning

confidence: 57%

Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action

Calland

Sahuc

Belouzard

et al. 2015

J Virol

122

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“…Presently, several entry inhibitors have been described, and their modes of action have been determined in mouse models or in cell culture (35). Among them, a plant-derived flavonoid (36) has been shown to inhibit the entry of all major HCV genotypes in vitro, while the green tea polyphenol epigallocatechin-3-gallate has been shown to inhibit primarily HCV entry (37,38) and secondarily HCV replication (39). Nonetheless, most entry inhibitors are in preclinical development, and only 2 of them are presently in clinical phase I/IIa of development.…”

Section: Discussionmentioning

confidence: 99%

Pan-genotypic Hepatitis C Virus Inhibition by Natural Products Derived from the Wild Egyptian Artichoke

Elsebai

Koutsoudakis

Saludes

et al. 2016

J Virol

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Hepatitis C virus (HCV) infection is the leading cause of chronic liver diseases. Water extracts of the leaves of the wild Egyptian artichoke (WEA) [Cynara cardunculus L. var. sylvestris (Lam.) Fiori] have been used for centuries in the Sinai Peninsula to treat hepatitis symptoms. Here we isolated and characterized six compounds from the water extracts of WEA and evaluated their HCV inhibition capacities in vitro. Importantly, two of these compounds, grosheimol and cynaropicrin, inhibited HCV with half-maximal effective concentrations (EC 50 s) in the low micromolar range. They inhibited HCV entry into target cells and were active against both cell-free infection as well as cell-cell transmission. Furthermore, the antiviral activity of both compounds was pan-genotypic as HCV genotypes 1a, 1b, 2b, 3a, 4a, 5a, 6a, and 7a were inhibited. Thus, grosheimol and cynaropicrin are promising candidates for the development of new pan-genotypic entry inhibitors of HCV infection. IMPORTANCEBecause there is no preventive HCV vaccine available today, the discovery of novel anti-HCV cell entry inhibitors could help develop preventive measures against infection. The present study describes two compounds isolated from the wild Egyptian artichoke (WEA) with respect to their structural elucidation, absolute configuration, and quantitative determination. Importantly, both compounds inhibited HCV infection in vitro. The first compound was an unknown molecule, and it was designated "grosheimol," while the second compound is the known molecule cynaropicrin. Both compounds belong to the group of sesquiterpene lactones. The mode of action of these compounds occurred during the early steps of the HCV life cycle, including cell-free and cell-cell infection inhibition. These natural compounds present promising candidates for further development into anti-HCV therapeutics. Hepatitis C virus (HCV) is an enveloped, positive-strand RNA virus classified as a separate genus (Hepacivirus) within the Flaviviridae family. It shows a high degree of genetic diversity, with 7 major circulating genotypes (1). HCV is mainly transmitted through exposure to HCV-contaminated blood. Most infections remain persistent, summing up to an estimated 150 million chronic HCV carriers worldwide (2). As persistent HCV infection frequently causes chronic hepatitis that can progress to liver cirrhosis and liver cell carcinoma, it is a major threat to human health (3, 4).Treatment options for chronically infected individuals have dramatically improved over the last few years. This has been due to the development of highly potent direct-acting antivirals (DAAs) that increased sustained response rates to over 90%, even in interferon-free combinations (5). Currently approved DAAs include NS3/4A protease inhibitors (telaprevir, boceprevir, and simeprevir), NS5A inhibitors (daclatasvir and ledipasvir), and the NS5B polymerase inhibitor sofosbuvir. Further antiviral drugs are in clinical trials and are about to be approved. Nonetheless, the rapid replication of HCV, al...

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“…It had previously been suggested that EGCG inhibits the essential NS3/4A serine protease of HCV (Zuo et al, 2007); however, these assays were performed in a cell-free system and this observation could not be validated in an HCV replication setting (Ciesek et al, 2011;Calland et al, 2012). Chen et al (2012) reported a slight inhibition (two to threefold) of HCV RNA replication with JFH1 and Con1 constructs in tissue culture, but only at a very high concentration (80 mM) of EGCG. Other catechins, such as EGC, EC and ECG, did not have such a strong inhibitory effect as EGCG, which suggests that inhibition of HCV entry is unique to EGCG and not shared by other green tea catechins (Ciesek et al, 2011).…”

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confidence: 97%

“…Therefore, more effective therapies that are applicable for all viral genotypes and with fewer side effects are needed. For instance, in respect of liver transplantation for HCV-associated end-stage liver disease, the ability to block viral cell entry would help to minimize the currently universal re-infection of the donor liver by virions in the blood.Recently, in the search for new antiviral molecules, three independent groups have identified EGCG as a potent inhibitor of the HCV entry pathway (Ciesek et al, 2011;Calland et al, 2012;Chen et al, 2012). Ciesek and colleagues were initially working on the influence of semen on HCV infection and became interested in EGCG when it was reported that the green tea molecule counteracts semen-mediated enhancement of HIV infection (Hauber et al, 2009).…”

mentioning

confidence: 99%

“…Calland and co-workers became interested in testing EGCG because it was reported to increase lipid droplet formation and to impair lipoprotein secretion in hepatocytes, two cellular functions known to play a role in the life cycle of HCV (Li et al, 2006). In these three studies it was clearly demonstrated that entry of cell culture-derived particles (HCVcc) as well as HCV pseudoparticles (HCVpp) are inhibited by EGCG independent of the HCV genotype (Ciesek et al, 2011;Calland et al, 2012;Chen et al, 2012). This was also the case when primary human hepatocytes, which resemble more closely the natural reservoir for HCV, were used as target cells.…”

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confidence: 99%

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Anti‐infective properties of epigallocatechin‐3‐gallate (EGCG), a component of green tea

Steinmann

Buer

Pietschmann

et al. 2013

British J Pharmacology

441

313

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The consumption of green tea (Camellia sinensis) has been shown to have many physiological and pharmacological health benefits. In the past two decades several studies have reported that epigallocatechin-3-gallate (EGCG), the main constituent of green tea, has anti-infective properties. Antiviral activities of EGCG with different modes of action have been demonstrated on diverse families of viruses, such as Retroviridae, Orthomyxoviridae and Flaviviridae and include important human pathogens like human immunodeficiency virus, influenza A virus and the hepatitis C virus. Furthermore, the molecule interferes with the replication cycle of DNA viruses like hepatitis B virus, herpes simplex virus and adenovirus. Most of these studies demonstrated antiviral properties within physiological concentrations of EGCG in vitro. In contrast, the minimum inhibitory concentrations against bacteria were 10-100-fold higher. Nevertheless, the antibacterial effects of EGCG alone and in combination with different antibiotics have been intensively analysed against a number of bacteria including multidrug-resistant strains such as methicillin-resistant Staphylococcus aureus or Stenotrophomonas maltophilia. Furthermore, the catechin EGCG has antifungal activity against human-pathogenic yeasts like Candida albicans. Although the mechanistic effects of EGCG are not fully understood, there are results indicating that EGCG binds to lipid membranes and affects the folic acid metabolism of bacteria and fungi by inhibiting the cytoplasmic enzyme dihydrofolate reductase. This review summarizes the current knowledge and future perspectives on the antibacterial, antifungal and antiviral effects of the green tea constituent EGCG. Abbreviations AUC (0-•), area under the concentration-time curve from 0 h to infinity; AZT,

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

Cited by 92 publications

References 60 publications

Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action

Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action

Pan-genotypic Hepatitis C Virus Inhibition by Natural Products Derived from the Wild Egyptian Artichoke

Anti‐infective properties of epigallocatechin‐3‐gallate (EGCG), a component of green tea

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