title: Lucidone suppresses hepatitis C virus replication by Nrf2-mediated heme oxygenase-1 induction.
abstract: Upon screening of plant-derived natural products against hepatitis C virus (HCV) in the replicon system, we demonstrate that lucidone, a phytocompound, isolated from the fruits of Lindera erythrocarpa Makino, significantly suppressed HCV RNA levels with 50% effective concentrations of 15 ± 0.5 μM and 20 ± 1.1 μM in HCV replicon and JFH-1 infectious assays, respectively. There was no significant cytotoxicity observed at high concentrations, with a 50% cytotoxic concentration of 620 ± 5 μM. In addition, lucidone significantly induced heme oxygenase-1 (HO-1) production and led to the increase of its product biliverdin for inducing antiviral interferon response and inhibiting HCV NS3/4A protease activity. Conversely, the anti-HCV activity of lucidone was abrogated by blocking HO-1 activity or silencing gene expression of HO-1 or NF-E2-related factor 2 (Nrf2) in the presence of lucidone, indicating that the anti-HCV action of lucidone was due to the stimulation of Nrf-2-mediated HO-1 expression. Moreover, the combination of lucidone and alpha interferon, the protease inhibitor telaprevir, the NS5A inhibitor BMS-790052, or the NS5B polymerase inhibitor PSI-7977, synergistically suppressed HCV RNA replication. These findings suggest that lucidone could be a potential lead or supplement for the development of new anti-HCV agent in the future.
authors.affiliation: Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Chen
authors.forename: Sheng-Yang
authors.initials: SY
authors.lastname: Wang
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Chiu
authors.forename: Chin-Kai
authors.initials: CK
authors.lastname: Tseng
authors.forename: Chun-Kuang
authors.initials: CK
authors.lastname: Lin
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Wang
authors.forename: Jin-Ching
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000998:Antiviral Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001664:Biliverdine / Q000096:biosynthesis; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000302:isolation & purification / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005638:Fruit / Q000737:chemistry; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D027443:Lindera / Q000737:chemistry*; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D012093:Replicon / Q000187:drug effects; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D001664:Biliverdine; D002352:Carrier Proteins; D003517:Cyclopentanes; D051547:Heme Oxygenase-1; D047908:Intracellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D017361:Viral Nonstructural Proteins; C495635:NFE2L2 protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C529637:lucidone