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

Abstract

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...

The wild Egyptian artichoke as a promising functional food for the treatment of hepatitis C virus as revealed via UPLC-MS and clinical trials

“…21 The anti-HCV activity of WEA was thus verified in the current clinical trial and in our previously reported in vitro studies. In Huber's study, it was reported that the artichoke extract of "Hepar SL forte ® " showed neither activity as anti-HCV, nor cholesterol and ALT lowering effects.…”

“…10 Apart from their nutritive value, artichoke extracts are well reported to exhibit antitumor, anti-hyperlipidemic, choleretic, anti-oxidant, hepatoprotective, and anti-inflammatory activities. 21 Cynaropicrin is the major bitter compound present in artichoke and its highest concentration found in leaves (especially in trichomes), and is almost absent in roots, stems and in completely developed inflorescences. 11 Huber et al 15 reported that the artichoke extract of "Hepar SL forte ® " showed no cholesterol lowering effects, although the cholesterol-lowering and hepatoprotective activities of artichoke were well verified by several other groups.…”

Oligonucleotide-Lipid Conjugates Forming G-Quadruplex Structures Are Potent and Pangenotypic Hepatitis C Virus Entry Inhibitors In Vitro and Ex Vivo

“…To assess whether lipoquads can inhibit HCV cell-to-cell transmission, we used an agarose overlay-based assay which inhibits cell-free virus, using a previously described infection reporter system (35). In this infection reporter system, Jc1 HCVcc-infected Huh7/Scr cells act as virus donor cells and uninfected Huh7.5/EGFP-NLS-IPS as acceptor cells (35,36). The latter cells stably express a chimeric enhanced green fluorescent protein (EGFP) which upon HCV infection is redistributed from mitochondria to the nucleus (a complete description of these cells is available in Materials and Methods).…”

Cynaropicrin Shows Antitumor Progression Potential in Colorectal Cancer through Mediation of the LIFR/STATs Axis

“…Cynaropicrin, a sesquiterpene lactone (STL), is a major biologically signi cant class of secondary metabolites in the artichoke (14). Cynaropicrin has been shown to possess various pharmacologic properties, such as anti-hepatitis C virus (15), anti-parasitic (16), anti-photo aging (17), anti-in ammatory (18), and anti-tumor properties. In human leukemia and prostate cancer cells, cynaropicrin is able to induce glutathione depletion and result in S-glutathionylation of STAT3, leading to down-regulation of STAT3-dependent gene expression and chemosensitization of tumor cells to chemotherapy (19).…”