Hepatitis C Virus and Natural Compounds: A New Antiviral Approach?

Calland, Noémie; Dubuisson, Jean; Rouillé, Yves; Séron, Karin

doi:10.3390/v4102197

Cited by 125 publications

(95 citation statements)

References 108 publications

(140 reference statements)

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“…Indeed, the improvement of hepatitis C treatment efficacy by the use of costly DAAs is predicted to have a low impact on the reduction of hepatitis C disease in these countries (13,14). In the last few years, reports on the identification of natural molecules of plant origin with anti-HCV activities have emerged (15,16). The most-studied plant extract is silymarin, an extract of the milk thistle plant that was used for years to treat liver diseases and has been proved to inhibit HCV infection at different steps of the viral life cycle and to display a hepatoprotective capacity (17).…”

mentioning

confidence: 99%

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

Calland

Sahuc

Belouzard

et al. 2015

J Virol

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129

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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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mentioning

confidence: 99%

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

Calland

Sahuc

Belouzard

et al. 2015

J Virol

Self Cite

129

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“…The isolation of this compound from fungal metabolites and its chemical identification have been reported (40). A number of small molecules derived from natural sources have been reported to be inhibitors of vial infections, including those of human immunodeficiency virus, HCV, herpesviruses, and influenza virus (41)(42)(43)(44)(45). However, the poor understanding of the mode of action in most of these cases has hampered the development of antiviral drugs based on these findings, suggesting that mechanis- tic analysis, especially the identification of the target molecule, is a very important issue for drug development.…”

Section: Discussionmentioning

confidence: 99%

A Novel Tricyclic Polyketide, Vanitaracin A, Specifically Inhibits the Entry of Hepatitis B and D Viruses by Targeting Sodium Taurocholate Cotransporting Polypeptide

Kaneko

Watashi

Kamisuki

et al. 2015

J Virol

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Anti-hepatitis B virus (HBV) drugs are currently limited to nucleos(t)ide analogs (NAs) and interferons. A challenge of drug development is the identification of small molecules thatC hronic hepatitis B virus (HBV) infection, constituting a public health problem, with an estimated 240 million carriers worldwide (1), elevates the risk of development of liver cirrhosis and hepatocellular carcinoma (2). Antiviral agents against HBV include nucleos(t)ide analogs (NAs) and interferons (IFNs), which can achieve significant reductions in HBV loads (3). Although IFN-␣ and its pegylated form (peg-IFN-␣) modulate host immune responses to HBV infection or directly inhibit HBV replication in hepatocytes, these regimens show low tolerability because of serious adverse effects (3, 4). NAs, including lamivudine (LMV), adefovir, entecavir (ETV), tenofovir, and telbivudine, inhibit reverse transcription to suppress HBV replication, but longterm treatment with some of these NAs often results in selection for a significant number of drug-resistant viruses, which decreases treatment efficacy; i.e., the introduction of two substitutions, L180M and M204V, in the polymerase region leads to resistance to LMV, and an additional mutation of either T184, S202, or M250 with the L180M/M204V mutations confers further ETV resistance (5). More notably, it is difficult for the above-mentioned anti-HBV drugs to completely eliminate HBV from infected cells. Future antiviral strategies include multidrug treatment with an existing drug and a new anti-HBV agent. Consequently, there is a

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“…During the past several decades a great deal of research has been invested natural products from medicinal plants due to the advantages of lower cost, fewer adverse effects, and high chemical diversity of these biologically active molecules. Many plant phytochemicals, such as flavonoids, terpenoids, lignin, alkaloids, tannins, polyphenolics, coumarins, saponins, and chlorophyllins, are reported to have anti-HCV activity (18)(19)(20)(21)(22)(23)(24)(25)(26). Thus, natural products from medicinal plants represent an alternative approach to controlling HCV infections.…”

Section: Introductionmentioning

confidence: 99%

Anti-Hepatitis C Virus Activity of a Crude Extract from Longan (<i>Dimocarpus longan</i> Lour.) Leaves

et al. 2016

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SUMMARY:Infection with hepatitis C virus (HCV) results in hepatitis C, a disease characterized by chronic infection, cirrhosis, and hepatocellular carcinoma. Currently, the standard therapy is a combination of pegylated interferon-a plus ribavirin with NS3 protease inhibitors. Addition of NS3 protease inhibitors to the standard therapy improves response rates; however, use of NS3 protease inhibitors is also associated with significant adverse effects and an increase in the overall cost of treatment. Therefore, there is a need to develop safe and inexpensive drugs for the treatment of HCV infections. In this study, we examined the antiviral activity of a crude extract from Dimocarpus longan leaves against HCV (genotype 2a strain JFH1). The D. longan crude extract (DL-CE) exhibited anti-HCV activity with a 50z effective concentration (EC 50 ) of 19.4 mg/ml without cytotoxicity. A time-of-addition study demonstrated that DL-CE has anti-HCV activity at both the entry and post-entry steps and markedly blocks the viral entry step through direct virucidal activity with marginal inhibition of virion assembly. Co-treatment of DL-CE with cyclosporine A, an immunosuppressant or telaprevir, an NS3 protease inhibitor, resulted in additive and synergistic antiviral effects, respectively. Our findings suggest that DL-CE may be useful as an add-on therapy candidate for treating HCV infections.

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Hepatitis C Virus and Natural Compounds: A New Antiviral Approach?

Cited by 125 publications

References 108 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

A Novel Tricyclic Polyketide, Vanitaracin A, Specifically Inhibits the Entry of Hepatitis B and D Viruses by Targeting Sodium Taurocholate Cotransporting Polypeptide

Anti-Hepatitis C Virus Activity of a Crude Extract from Longan (<i>Dimocarpus longan</i> Lour.) Leaves

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