Abstract
The current treatments of chronic hepatitis B (CHB) face a limited choice of vaccine, antibody and antiviral agents. The development of additional antiviral agents is still needed for improvement of CHB therapy. In this study, we established a screening system in order to identify compounds inhibiting the core promoter activity of hepatitis B virus (HBV). We prepared 80 extracts of marine organisms from the coral reefs of Indonesia and screened them by using this system. Eventually, two extracts showed high inhibitory activity (>95%) and low cytotoxicity (66% to 77%). Solvent fractionation, column chromatography and NMR analysis revealed that 3,5-dibromo-2-(2,4-dibromophenoxy)-phenol (compound 1) and 3,4,5-tribromo-2-(2,4-dibromophenoxy)-phenol (compound 2), which are classified as polybrominated diphenyl ethers (PBDEs), were identified as anti-HBV agents in the extracts. Compounds 1 and 2 inhibited HBV core promoter activity as well as HBV production from HepG2.2.15.7 cells in a dose-dependent manner. The EC50 values of compounds 1 and 2 were 0.23 and 0.80 µM, respectively, while selectivity indexes of compound 1 and 2 were 18.2 and 12.8, respectively. These results suggest that our cell-based HBV core promoter assay system is useful to determine anti-HBV compounds, and that two PBDE compounds are expected to be candidates of lead compounds for the development of anti-HBV drugs.
Highlights
Hepatitis B virus (HBV) infection is a serious public health problem worldwide, with more than 240 million people estimated to be chronically infected [1]
We established a screening system to identify compounds inhibiting hepatitis B virus (HBV) core promoter activity and screened 80 extracts of marine organisms collected from the coral reefs of Indonesia in order to identify anti-HBV agents
The core promoter consists of CURS and basal core promoter (BCP) (Figure 1A) and is responsible for transcription of 3.5 kb mRNA, pregenomic RNA (pgRNA) [4]
Summary
Hepatitis B virus (HBV) infection is a serious public health problem worldwide, with more than 240 million people estimated to be chronically infected [1]. The currently available antiviral agents for the treatment of chronic HBV infection are classified as follows: (1) immunomodulatory agents, such as conventional interferon-alpha and pegylated interferon-alpha; and (2) oral nucleoside/nucleotide analogues (NAs), such as three nucleoside (lamivudine, entecavir and telbivudine) and two nucleotide analogues (adefovir and tenofovir). Treatments with these agents are capable of preventing disease progression to liver cirrhosis and hepatocellular carcinoma, resulting in improvement of the survival rate of patients with chronic HBV infections [11,12,13]. We established a screening system to identify compounds inhibiting HBV core promoter activity and screened 80 extracts of marine organisms collected from the coral reefs of Indonesia in order to identify anti-HBV agents
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