Identification and Biochemical Characterization of Halisulfate 3 and Suvanine as Novel Inhibitors of Hepatitis C Virus NS3 Helicase from a Marine Sponge
Atsushi Furuta,
Kazi Abdus Salam,
Idam Hermawan,
Nobuyoshi Akimitsu,
Junichi Tanaka,
Hidenori Tani,
Atsuya Yamashita,
Kohji Moriishi,
Masamichi Nakakoshi,
Masayoshi Tsubuki,
Poh Wee Peng,
Youichi Suzuki,
Naoki Yamamoto,
Yuji Sekiguchi,
Satoshi Tsuneda,
Naohiro Noda
Affiliations
Atsushi Furuta
Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan
Kazi Abdus Salam
Radioisotope Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Idam Hermawan
Department of Chemistry, Biology and Marine Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan
Nobuyoshi Akimitsu
Radioisotope Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Junichi Tanaka
Department of Chemistry, Biology and Marine Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan
Hidenori Tani
Research Institute for Environmental Management Technology, National Institute of Advanced Industrial Science and Technology (AIST), 16-1 Onogawa, Tsukuba, Ibaraki 305-8569, Japan
Atsuya Yamashita
Department of Microbiology, Division of Medicine, Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan
Kohji Moriishi
Department of Microbiology, Division of Medicine, Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan
Masamichi Nakakoshi
Institute of Medical Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
Masayoshi Tsubuki
Institute of Medical Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
Poh Wee Peng
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, #15-02, Level 15, Singapore 117599, Singapore
Youichi Suzuki
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, #15-02, Level 15, Singapore 117599, Singapore
Naoki Yamamoto
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, #15-02, Level 15, Singapore 117599, Singapore
Yuji Sekiguchi
Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan
Satoshi Tsuneda
Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan
Naohiro Noda
Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan
Hepatitis C virus (HCV) is an important etiological agent that is responsible for the development of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV nonstructural protein 3 (NS3) helicase is a possible target for novel drug development due to its essential role in viral replication. In this study, we identified halisulfate 3 (hal3) and suvanine as novel NS3 helicase inhibitors, with IC50 values of 4 and 3 µM, respectively, from a marine sponge by screening extracts of marine organisms. Both hal3 and suvanine inhibited the ATPase, RNA binding, and serine protease activities of NS3 helicase with IC50 values of 8, 8, and 14 µM, and 7, 3, and 34 µM, respectively. However, the dengue virus (DENV) NS3 helicase, which shares a catalytic core (consisting mainly of ATPase and RNA binding sites) with HCV NS3 helicase, was not inhibited by hal3 and suvanine, even at concentrations of 100 µM. Therefore, we conclude that hal3 and suvanine specifically inhibit HCV NS3 helicase via an interaction with an allosteric site in NS3 rather than binding to the catalytic core. This led to the inhibition of all NS3 activities, presumably by inducing conformational changes.
