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Inhibition of hepatitis B virus gene expression and replication by arylnaphthalene lignan analogues HE‐145–111
Author(s) -
Yeh Sheau Farn,
Lin Chih Hsiu
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.805.2
Subject(s) - hepatitis b virus , microbiology and biotechnology , promoter , reporter gene , mutant , virology , hepatocyte nuclear factor 4 , virus , biology , luciferase , chemistry , gene expression , viral replication , gene , transfection , biochemistry , transcription factor , nuclear receptor
We have previously reported a natural product, Heliothanxin (HE‐145) from Taiwania cryptomerioides Hayata to suppress HBV gene expression and replication in HCC cells. A series of helioxanthin analogues were synthesized and evaluated for their anti‐hepatitis B virus activity. Among them, compound HE‐145–111 is one of the most effective anti‐HBV agents. We found that HE‐145–111 suppressed not only wild type but also lamivudine‐resistant mutant HBV virus production by human hepatoma cells. To understand the molecular mechanism of HE‐145–111 on HBV gene expression, the effects of HE‐145–111 on four viral promoter activities using luciferase as a reporter were examined. It was found that HE‐145–111 selectively suppresses core promoter (CP). The suppressive effects of HE‐145–111 CP activity is liver‐specific because no suppressive activity of HE‐145–111 was observed when CP activity was assayed in non‐liver cells such as HeLa or 293T. Furthermore, we identified that the nt1656–1708 which contains hepatocyte nuclear factor 4£\ (HNF4£\) binding sequence as a response element of HE‐145–111 in HBV core promoter using serial deletion mutants of core promoter analysis. HE‐145–111 may represent a novel class of anti‐HBV drug which suppresses the HBV core promoter activity may act through modulating hepatic transcriptional machinery to suppress HBV viral gene expression and virus production.