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

    Research output: Contribution to journalArticle

    9 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)462-476
    Number of pages15
    JournalMarine Drugs
    Volume12
    Issue number1
    DOIs
    Publication statusPublished - 2014 Jan

    Fingerprint

    Porifera
    Hepacivirus
    Proteins
    Inhibitory Concentration 50
    Adenosine Triphosphatases
    Catalytic Domain
    RNA
    Allosteric Site
    Aquatic Organisms
    Dengue Virus
    halisulfate 3
    suvanine
    Serine Proteases
    Chronic Hepatitis
    Liver Cirrhosis
    Hepatocellular Carcinoma
    Binding Sites
    Pharmaceutical Preparations

    Keywords

    • Dengue virus
    • Halisulfate 3
    • Hepatitis C virus
    • Marine organism
    • NS3 helicase
    • Suvanine

    ASJC Scopus subject areas

    • Drug Discovery

    Cite this

    Identification and biochemical characterization of halisulfate 3 and suvanine as novel inhibitors of hepatitis C virus NS3 helicase from a marine sponge. / Furuta, Atsushi; Salam, Kazi Abdus; Hermawan, Idam; Akimitsu, Nobuyoshi; Tanaka, Junichi; Tani, Hidenori; Yamashita, Atsuya; Moriishi, Kohji; Nakakoshi, Masamichi; Tsubuki, Masayoshi; Peng, Poh Wee; Suzuki, Youichi; Yamamoto, Naoki; Sekiguchi, Yuji; Tsuneda, Satoshi; Noda, Naohiro.

    In: Marine Drugs, Vol. 12, No. 1, 01.2014, p. 462-476.

    Research output: Contribution to journalArticle

    Furuta, A, Salam, KA, Hermawan, I, Akimitsu, N, Tanaka, J, Tani, H, Yamashita, A, Moriishi, K, Nakakoshi, M, Tsubuki, M, Peng, PW, Suzuki, Y, Yamamoto, N, Sekiguchi, Y, Tsuneda, S & Noda, N 2014, 'Identification and biochemical characterization of halisulfate 3 and suvanine as novel inhibitors of hepatitis C virus NS3 helicase from a marine sponge' Marine Drugs, vol. 12, no. 1, pp. 462-476. https://doi.org/10.3390/md12010462
    Furuta, Atsushi ; Salam, Kazi Abdus ; Hermawan, Idam ; Akimitsu, Nobuyoshi ; Tanaka, Junichi ; Tani, Hidenori ; Yamashita, Atsuya ; Moriishi, Kohji ; Nakakoshi, Masamichi ; Tsubuki, Masayoshi ; Peng, Poh Wee ; Suzuki, Youichi ; Yamamoto, Naoki ; Sekiguchi, Yuji ; Tsuneda, Satoshi ; Noda, Naohiro. / Identification and biochemical characterization of halisulfate 3 and suvanine as novel inhibitors of hepatitis C virus NS3 helicase from a marine sponge. In: Marine Drugs. 2014 ; Vol. 12, No. 1. pp. 462-476.
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    abstract = "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.",
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