Unique antiviral mechanism discovered in anti-hepatitis B virus research with a natural product analogue.
Helioxanthin is a natural product that inhibits the replication of a number of viruses. We found that a previously undescribed helioxanthin analogue, 8-1, exhibited potent anti-hepatitis B virus (HBV) activity with little cytotoxicity. 8-1 suppressed both HBV RNA and protein expression, as well as DNA replication of both wild-type and 3TC-resistant virus. Time-course analyses revealed that RNA expression was blocked first after treatment with 8-1, followed by viral proteins, and then DNA. 8-1 inhibited the activity of all HBV promoters by decreasing the binding of hepatocyte nuclear factor 4 (HNF-4), HNF-3, and fetoprotein factor to the precore/core promoter enhancer II region. The amount of HNF-4 and HNF-3 was decreased posttranscriptionally by 8-1 in HBV-producing cells, but not in HBV-negative cells. Therefore, 8-1 suppresses HBV replication by posttranscriptional down-regulation of critical transcription factors in HBV-producing cells, thus diminishing HBV promoter activity and blocking viral gene expression and replication. This mechanism is unique and different from other anti-HBV compounds previously described.
Ying
Chunxiao
C
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066, USA.
Li
Ying
Y
Leung
Chung-Hang
CH
Robek
Michael D
MD
Cheng
Yung-Chi
YC
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D052117:Benzodioxoles / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004279:DNA, Viral / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics; D051536:Hepatocyte Nuclear Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D017705:Lignans; D008954:Models, Biological; D010793:Phthalazines / Q000737:chemistry / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D012367:RNA, Viral / Q000378:metabolism; D013816:Thermodynamics; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014764:Viral Proteins / Q000378:metabolism; D014970:Xanthines / Q000737:chemistry / Q000494:pharmacology*
C520741:8-1 compound; D000998:Antiviral Agents; D052117:Benzodioxoles; D004279:DNA, Viral; D051536:Hepatocyte Nuclear Factors; D017705:Lignans; D010793:Phthalazines; D012367:RNA, Viral; D014764:Viral Proteins; D014970:Xanthines; C505802:helioxanthin; D019259:Lamivudine