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• Yamashita, A
• Salam, K
• Furuta, A
• Matsuda, Y
• Fujita, O
• Tani, H
• Fujita, Y
• Fujimoto, Y
• Ikeda, M
• Kato, N
• Sakamoto, N
• Maekawa, S
• Enomoto, N
• Nakakoshi, M
• Tsubuki, M
• Sekiguchi, Y
• Tsuneda, S
• Akimitsu, N
• Noda, N
• Tanaka, J
• Moriishi, K
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• Yamashita, A
• Salam, K
• Furuta, A
• Matsuda, Y
• Fujita, O
• Tani, H
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• Yamashita, A
• Salam, K
• Furuta, A
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• Fujita, O
• Tani, H
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• Ikeda, M
• Kato, N
• Sakamoto, N
• Maekawa, S
• Enomoto, N
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• Tsubuki, M
• Sekiguchi, Y
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Mar. Drugs 2012, 10(4), 744-761; doi:10.3390/md10040744

Article

Inhibition of Hepatitis C Virus Replication and Viral Helicase by Ethyl Acetate Extract of the Marine Feather Star Alloeocomatella polycladia

Atsuya Yamashita ¹ , Kazi Abdus Salam ^2,† , Atsushi Furuta ^3,4,† , Yasuyoshi Matsuda ^3,4 , Osamu Fujita ^3,4 , Hidenori Tani ² , Yoshihisa Fujita ^5,6 , Yuusuke Fujimoto ¹ , Masanori Ikeda ⁷ , Nobuyuki Kato ⁷ , Naoya Sakamoto ⁸ , Shinya Maekawa ⁹ , Nobuyuki Enomoto ⁹ , Masamichi Nakakoshi ¹⁰ , Masayoshi Tsubuki ¹⁰ , Yuji Sekiguchi ³ , Satoshi Tsuneda ⁴ , Nobuyoshi Akimitsu ² , Naohiro Noda ³ , Junichi Tanaka ^11,*  and Kohji Moriishi ^1,*

¹ Department of Microbiology, Division of Medicine, Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan ² Radioisotope Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan ³ Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan ⁴ Department of Life Science and Medical Bio-Science, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan ⁵ University Education Center, University of the Ryukyus, Okinawa, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan ⁶ Marine Learning Center, 2-95-101 Miyagi, Chatan, Okinawa 901-0113, Japan ⁷ Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, 2-5-1 Shikata-cho, Okayama 700-8558, Japan ⁸ Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan ⁹ First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan ¹⁰ Institute of Medical Chemistry, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan ¹¹ Department of Chemistry, Biology and Marine Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan ^† These authors contributed equally to this work.

* Authors to whom correspondence should be addressed.

Received: 9 February 2012; in revised form: 17 March 2012 / Accepted: 19 March 2012 / Published: 28 March 2012

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Abstract: Hepatitis C virus (HCV) is a causative agent of acute and chronic hepatitis, leading to the development of hepatic cirrhosis and hepatocellular carcinoma. We prepared extracts from 61 marine organisms and screened them by an in vitro fluorescence assay targeting the viral helicase (NS3), which plays an important role in HCV replication, to identify effective candidates for anti-HCV agents. An ethyl acetate-soluble fraction of the feather star Alloeocomatella polycladia exhibited the strongest inhibition of NS3 helicase activity, with an IC₅₀ of 11.7 µg/mL. The extract of A. polycladia inhibited interaction between NS3 and RNA but not ATPase of NS3. Furthermore, the replication of the replicons derived from three HCV strains of genotype 1b in cultured cells was suppressed by the extract with an EC₅₀ value of 23 to 44 µg/mL, which is similar to the IC₅₀ value of the NS3 helicase assay. The extract did not induce interferon or inhibit cell growth. These results suggest that the unknown compound(s) included in A. polycladia can inhibit HCV replication by suppressing the helicase activity of HCV NS3. This study may present a new approach toward the development of a novel therapy for chronic hepatitis C.

Keywords: marine organism; Alloeocomatella polycladia; hepatitis C virus; NS3 helicase

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