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Mar. Drugs 2015, 13(11), 6759-6773; doi:10.3390/md13116759

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
2
Department of Chemistry, Biology and Marine Science, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan
3
Department of Chemistry, Faculty of Science, Lampung University, Jl. Sumantri Brodjonegoro No. 1, Bandar Lampung 35145, Indonesia
4
Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
5
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
6
Naturalis, National Museum of Natural History, P.O. Box 9517, Leiden 2300 RA, The Netherlands
7
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
Received: 19 September 2015 / Revised: 23 October 2015 / Accepted: 23 October 2015 / Published: 6 November 2015
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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. 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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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

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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