Unique antiviral mechanism discovered in anti-hepatitis B virus research with a natural product analogue

doi:10.1073/pnas.0609883104

Unique antiviral mechanism discovered in anti-hepatitis B virus research with a natural product analogue

Departments of *Pharmacology and
^‡Pathology, Yale University School of Medicine, New Haven, CT 06520-8066

Edited by Peter M. Howley, Harvard Medical School, Boston, MA, and approved April 3, 2007 (received for review November 7, 2006)

Abstract

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.

Footnotes

^§To whom correspondence should be addressed at:
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066.
E-mail: yccheng{at}yale.edu
Author contributions: M.D.R. and Y.-C.C. designed research; C.Y., Y.L., and C.-H.L. performed research; and C.Y., Y.L., C.-H.L., M.D.R., and Y.-C.C. wrote the paper.
↵ ^†Present address: 6F, Fu Xing Plaza, 109 YanDang Road, Shanghai, 200020, China.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Abbreviations:

CC50,

concentration of 50% cytotoxicity;

FTF,

Fetoprotein transcription factor;

HBV,

hepatitis B virus;

HNF,

hepatocyte nuclear factor;

pgRNA,

pregenomic RNA;

RT,

room temperature.