title: Artemisinin analogues as potent inhibitors of in vitro hepatitis C virus replication.
abstract: We reported previously that Artemisinin (ART), a widely used anti-malarial drug, is an inhibitor of in vitro HCV subgenomic replicon replication. We here demonstrate that ART exerts its antiviral activity also in hepatoma cells infected with full length infectious HCV JFH-1. We identified a number of ART analogues that are up to 10-fold more potent and selective as in vitro inhibitors of HCV replication than ART. The iron donor Hemin only marginally potentiates the anti-HCV activity of ART in HCV-infected cultures. Carbon-centered radicals have been shown to be critical for the anti-malarial activity of ART. We demonstrate that carbon-centered radicals-trapping (the so-called TEMPO) compounds only marginally affect the anti-HCV activity of ART. This provides evidence that carbon-centered radicals are not the main effectors of the anti-HCV activity of the Artemisinin. ART and analogues may possibly exert their anti-HCV activity by the induction of reactive oxygen species (ROS). The combined anti-HCV activity of ART or its analogues with L-N-Acetylcysteine (L-NAC) [a molecule that inhibits ROS generation] was studied. L-NAC significantly reduced the in vitro anti-HCV activity of ART and derivatives. Taken together, the in vitro anti-HCV activity of ART and analogues can, at least in part, be explained by the induction of ROS; carbon-centered radicals may not be important in the anti-HCV effect of these molecules.
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Susan
authors.initials: S
authors.lastname: Obeid
authors.affiliation: Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Leuven, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Alen
authors.affiliation: Institute of Marine Biochemistry, Vietnam Academy of Science and Technology, Hanoi, Vietnam.
authors.forename: Van Hung
authors.initials: VH
authors.lastname: Nguyen
authors.affiliation: Institute of Marine Biochemistry, Vietnam Academy of Science and Technology, Hanoi, Vietnam.
authors.forename: Van Cuong
authors.initials: VC
authors.lastname: Pham
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, University Ghent, Ghent, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Meuleman
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.affiliation: Institute of Marine Biochemistry, Vietnam Academy of Science and Technology, Hanoi, Vietnam.
authors.forename: Thanh Nguyen
authors.initials: TN
authors.lastname: Le
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Dehaen
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Paeshuyse
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D037621:Artemisinins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides / Q000494:pharmacology; D058492:Drug Repositioning; D006427:Hemin / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D000975:Antioxidants; D000998:Antiviral Agents; D037621:Artemisinins; D003497:Cyclic N-Oxides; D012367:RNA, Viral; D017382:Reactive Oxygen Species; D006427:Hemin; C031327:artemisinin; C003959:TEMPO; D000111:Acetylcysteine