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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antiviral Agents / isolation & purification
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Antiviral Agents / pharmacology*
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Biliverdine / biosynthesis
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / metabolism
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Cell Line, Tumor
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Cyclopentanes / isolation & purification
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Cyclopentanes / pharmacology*
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Drug Therapy, Combination
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Fruit / chemistry
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Gene Expression Regulation
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Heme Oxygenase-1 / antagonists & inhibitors
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Heme Oxygenase-1 / genetics*
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Heme Oxygenase-1 / metabolism
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Hepacivirus / drug effects*
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Hepacivirus / physiology
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Hepatocytes / drug effects*
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Hepatocytes / metabolism
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Hepatocytes / virology
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Host-Pathogen Interactions
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Humans
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Intracellular Signaling Peptides and Proteins
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Lindera / chemistry*
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NF-E2-Related Factor 2 / antagonists & inhibitors
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NF-E2-Related Factor 2 / genetics*
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NF-E2-Related Factor 2 / metabolism
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Protease Inhibitors / pharmacology
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RNA, Small Interfering / genetics
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Replicon / drug effects
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Viral Load / drug effects
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Viral Nonstructural Proteins / antagonists & inhibitors
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Viral Nonstructural Proteins / metabolism
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Virus Replication / drug effects
Substances
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Antiviral Agents
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Carrier Proteins
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Cyclopentanes
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Intracellular Signaling Peptides and Proteins
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NF-E2-Related Factor 2
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NFE2L2 protein, human
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NS3 protein, hepatitis C virus
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NS4A cofactor peptide, Hepatitis C virus
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Protease Inhibitors
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RNA, Small Interfering
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Viral Nonstructural Proteins
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lucidone
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Heme Oxygenase-1
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Biliverdine