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

Marine Drugs

Atsuya Yamashita⁶  Yuusuke Fujimoto⁶  Mayumi Tamaki¹  Andi Setiawan⁴  Tomohisa Tanaka⁶  Kaori Okuyama-Dobashi⁶  Hirotake Kasai⁶  Koichi Watashi⁵  Takaji Wakita⁵  Masaaki Toyama²  Masanori Baba²  Nicole J. de Voogd⁷  Shinya Maekawa³  Nobuyuki Enomoto³  Junichi Tanaka¹  Kohji Moriishi⁶ 

[1] Department of Chemistry, Biology and Marine Science, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan; E-Mail:;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; E-Mails:;The First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan; E-Mails:;Department of Chemistry, Faculty of Science, Lampung University, Jl. Sumantri Brodjonegoro No. 1, Bandar Lampung 35145, Indonesia; E-Mail:;Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; E-Mails:;Department of Microbiology, Division of Medical Sciences, Graduate School of Interdisciplinary Research, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan; E-Mails:;Naturalis, National Museum of Natural History, P.O. Box 9517, Leiden 2300 RA, The Netherlands; E-Mail:

关键词: marine organism;    hepatitis B virus;    HBV;    HBV core promoter;    high-throughput screening;    antiviral agent;   

DOI  :  10.3390/md13116759

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.