title: Inhibition of hepatitis B virus gene expression and replication by helioxanthin and its derivative.
abstract: Chronic hepatitis B virus (HBV) infection continues to be an important worldwide cause of morbidity and mortality. All the currently approved therapeutic drugs have their limitations: interferon-alpha (IFN-alpha) has limited efficacy and a high incidence of adverse effects; nucleoside analogues are very efficient HBV DNA inhibitors, but resistance occurs eventually. Therefore, it is important to develop new non-nucleoside/nucleotide agents with different modes of action that can be used for antiviral combination therapy. Here, we report on a novel class of compounds, helioxanthin and its derivative 5-4-2, which had potent anti-HBV activities in HepG2.2.15 cells, with the EC50s of 1 and 0.08 microM, respectively. The lamivudine-resistant HBV, L526M/M550V double mutant strain, was also sensitive to helioxanthin and 5-4-2. This class of compounds not only inhibited HBV DNA, but also decreased HBV mRNA and HBV protein expression. The EC50 of HBV DNA inhibition was consistent with the EC50 of HBV 3.5 Kb transcript inhibition, which was 1 and 0.09 microM for helioxanthin and 5-4-2 respectively. Western blot analysis of cell lysate from HepG2.2.15 cells showed that the core protein expression decreased in a dose-dependent manner after drug treatment. In conclusion, helioxanthin and 5-4-2 are potentially unique new anti-HBV agents, which possess a different mechanism of action from existing therapeutic drugs. Both compounds inhibited HBV RNA and protein expression in addition to inhibiting HBV DNA.
authors: Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
authors: Ying
authors: Y
authors: Li
authors: Lei
authors: L
authors: Fu
authors: Hosup
authors: H
authors: Yeo
authors: Ju-Liang
authors: JL
authors: Zhu
authors: Chen-Kung
authors: CK
authors: Chou
authors: Yueh-Hsiung
authors: YH
authors: Kou
authors: Sheau-Farn
authors: SF
authors: Yeh
authors: Elizabeth
authors: E
authors: Gullen
authors: David
authors: D
authors: Austin
authors: Yung-Chi
authors: YC
authors: Cheng
mesh_terms: D000998:Antiviral Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004279:DNA, Viral / Q000037:antagonists & inhibitors; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006801:Humans; D017705:Lignans; D012367:RNA, Viral / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014758:Viral Core Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*; D014970:Xanthines / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000633:toxicity*
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D017705:Lignans; D012367:RNA, Viral; D014758:Viral Core Proteins; D014970:Xanthines; C505802:helioxanthin