A Plant-Derived Flavonoid Inhibits Entry of All HCV Genotypes Into Human Hepatocytes

Haid, Sibylle; Novodomskà, Alexandra; Gentzsch, Juliane; Grethe, Christina; Geuenich, Silvia; Bankwitz, Dorothea; Chhatwal, Patrick; Jannack, Beate; Hennebelle, Thierry; Bailleul, François; Keppler, Oliver T.; Poenisch, Marion; Bartenschlager, Ralf; Hernandez, Céline; Lemasson, Matthieu; Rosenberg, Arielle R.; Wong‐Staal, Flossie; Davioud‐Charvet, Elisabeth; Pietschmann, Thomas

doi:10.1053/j.gastro.2012.03.036

Cited by 112 publications

(80 citation statements)

References 43 publications

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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%

“…These are the ITX5061 inhibitor of the scavenger receptor class B type I and erlotinib, a known compound that inhibits the epidermal growth factor alpha receptor. Very recently, the coadministration of the anti-SRBI mAb1671 with the DAA ciluprevir (protease inhibitor) in human liver-grafted mice offered the first preclinical in vivo evidence that addition of an entry inhibitor to an anti-HCV DAA regimen restricts the breakthrough of DAA-resistant viruses (36). Thus, they may present in the future an appropriate solution for (i) prevention of the liver graft infections that are universally observed when seropositive patients are not treated prior to liver transplantation and for (ii) treatment in combination with DAAs of difficult-totreat patients like those with liver cirrhosis and hepatocellular carcinoma.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Silymarin and its derived compound silibinin have been tested in liver transplant patients and nonresponder patients with a substantial positive effect (18)(19)(20). Moreover, some other purified molecules, like EGCG, ladanein, cucurmin, and saikosaponin b2, seem to be good candidates for use as HCV entry inhibitors (7,9,15,21,22).…”

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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“…Huh7 cells were transfected with JFH-1 RNA and seeded on six-well plates for 4 h before treatment with TGN for 24 h. After 48 h of transfection, the cell supernatant was collected to measure the extracellular virus infectivity. The intracellular virions of the HCV-electroporated cells were collected by three freeze-thaw cycles in liquid nitrogen and a 37 uC incubator as described previously (Haid et al, 2012). Virus infectivity was detected by inoculating naïve Huh7 cells.…”

Section: Methodsmentioning

confidence: 99%

Trachelogenin, a novel inhibitor of hepatitis C virus entry through CD81

Qian

Jin

Chen

et al. 2016

Journal of General Virology

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Although much progress has been made in antiviral agents against hepatitis C virus (HCV) in recent years, novel HCV inhibitors with improved efficacy, optimized treatment duration and more affordable prices are still urgently needed. Here, we report the identification of a natural plant-derived lignan, trachelogenin (TGN), as a potent entry inhibitor of HCV without genotype specificity, and with low cytotoxicity. TGN was extracted and purified from Caulis trachelospermi, a traditional Chinese herb with anti-inflammatory and analgesic effects. A crucial function of TGN was the inhibition of HCV entry during a post-binding step without affecting virus replication, translation, assembly and release. TGN blocked virus infection by interfering with the normal interactions between HCV glycoprotein E2 and the host entry factor CD81, which are key processes for valid virus entry. In addition, TGN diminished HCV cell-to-cell spread and exhibited additional synergistic effects when combined with IFN or telaprevir. In conclusion, this study highlights the effect of a novel HCV entry inhibitor, TGN, which has a target that differs from those of the current antiviral agents. Therefore, TGN is a potential candidate for future cocktail therapies to treat HCV-infected patients.

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A Plant-Derived Flavonoid Inhibits Entry of All HCV Genotypes Into Human Hepatocytes

Cited by 112 publications

References 43 publications

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

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

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

Trachelogenin, a novel inhibitor of hepatitis C virus entry through CD81

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