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Identification of Antiviral Agents Targeting Hepatitis B Virus Promoter from Extracts of Indonesian Marine Organisms by a Novel Cell-Based Screening Assay

1
Department of Microbiology, Division of Medical Sciences, Graduate School of Interdisciplinary Research, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan
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Department of Chemistry, Biology and Marine Science, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan
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Department of Chemistry, Faculty of Science, Lampung University, Jl. Sumantri Brodjonegoro No. 1, Bandar Lampung 35145, Indonesia
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Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
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Division of Antiviral Chemotherapy Center for Chronic Viral Disease, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
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Naturalis, National Museum of Natural History, P.O. Box 9517, Leiden 2300 RA, The Netherlands
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The First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan
*
Authors to whom correspondence should be addressed.
Academic Editor: Peer B. Jacobson
Mar. Drugs 2015, 13(11), 6759-6773; https://doi.org/10.3390/md13116759
Received: 19 September 2015 / Revised: 23 October 2015 / Accepted: 23 October 2015 / Published: 6 November 2015
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. View Full-Text
Keywords: marine organism; hepatitis B virus; HBV; HBV core promoter; high-throughput screening; antiviral agent marine organism; hepatitis B virus; HBV; HBV core promoter; high-throughput screening; antiviral agent
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Yamashita, A.; Fujimoto, Y.; Tamaki, M.; Setiawan, A.; Tanaka, T.; Okuyama-Dobashi, K.; Kasai, H.; Watashi, K.; Wakita, T.; Toyama, M.; Baba, M.; De Voogd, N.J.; Maekawa, S.; Enomoto, N.; Tanaka, J.; Moriishi, K. Identification of Antiviral Agents Targeting Hepatitis B Virus Promoter from Extracts of Indonesian Marine Organisms by a Novel Cell-Based Screening Assay. Mar. Drugs 2015, 13, 6759-6773.

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