Cholesterol sulfate as a potential inhibitor of hepatitis C virus NS3 helicase

Atsushi Furuta, Kazi Abdus Salam, Nobuyoshi Akimitsu, Junichi Tanaka, Hidenori Tani, Atsuya Yamashita, Kohji Moriishi, Masamichi Nakakoshi, Masayoshi Tsubuki, Yuji Sekiguchi, Satoshi Tsuneda, Naohiro Noda

    Research output: Contribution to journalArticle

    7 Citations (Scopus)

    Abstract

    Hepatitis C virus nonstructural protein 3 (NS3) helicase is a promising target for developing new therapeutics. In this study, we identified cholesterol sulfate (CS) as a novel NS3 helicase inhibitor (IC50 = 1.7 ± 0.2 μM with a Hill coefficient of 3.9) by screening the extracts from marine organisms. The lack of the sulfate group, sterol structure or alkyl side chain of CS diminished the inhibition, suggesting that an anion binding and hydrophobic region in NS3 may be a target site of CS. It was further found that CS partly inhibits NS3-RNA binding activity, but exerted no or less inhibition against ATPase and serine protease activities. Moreover, we demonstrated that CS probably does not bind to RNA. Our findings suggest that CS may inhibit NS3 helicase not by abolishing the other NS3 activities but by inducing conformational changes via interaction with possible allosteric sites of NS3.

    Original languageEnglish
    Pages (from-to)223-229
    Number of pages7
    JournalJournal of Enzyme Inhibition and Medicinal Chemistry
    Volume29
    Issue number2
    DOIs
    Publication statusPublished - 2014

    Fingerprint

    Hepacivirus
    Proteins
    Allosteric Site
    Aquatic Organisms
    RNA-Binding Proteins
    Serine Proteases
    Sterols
    Inhibitory Concentration 50
    Sulfates
    Anions
    Adenosine Triphosphatases
    cholesteryl sulfate
    RNA

    Keywords

    • Cholesterol sulfate
    • Hepatitis C virus
    • Marine organism
    • NS3 helicase

    ASJC Scopus subject areas

    • Drug Discovery
    • Pharmacology

    Cite this

    Furuta, A., Salam, K. A., Akimitsu, N., Tanaka, J., Tani, H., Yamashita, A., ... Noda, N. (2014). Cholesterol sulfate as a potential inhibitor of hepatitis C virus NS3 helicase. Journal of Enzyme Inhibition and Medicinal Chemistry, 29(2), 223-229. https://doi.org/10.3109/14756366.2013.766607

    Cholesterol sulfate as a potential inhibitor of hepatitis C virus NS3 helicase. / Furuta, Atsushi; Salam, Kazi Abdus; Akimitsu, Nobuyoshi; Tanaka, Junichi; Tani, Hidenori; Yamashita, Atsuya; Moriishi, Kohji; Nakakoshi, Masamichi; Tsubuki, Masayoshi; Sekiguchi, Yuji; Tsuneda, Satoshi; Noda, Naohiro.

    In: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 29, No. 2, 2014, p. 223-229.

    Research output: Contribution to journalArticle

    Furuta, A, Salam, KA, Akimitsu, N, Tanaka, J, Tani, H, Yamashita, A, Moriishi, K, Nakakoshi, M, Tsubuki, M, Sekiguchi, Y, Tsuneda, S & Noda, N 2014, 'Cholesterol sulfate as a potential inhibitor of hepatitis C virus NS3 helicase' Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 29, no. 2, pp. 223-229. https://doi.org/10.3109/14756366.2013.766607
    Furuta, Atsushi ; Salam, Kazi Abdus ; Akimitsu, Nobuyoshi ; Tanaka, Junichi ; Tani, Hidenori ; Yamashita, Atsuya ; Moriishi, Kohji ; Nakakoshi, Masamichi ; Tsubuki, Masayoshi ; Sekiguchi, Yuji ; Tsuneda, Satoshi ; Noda, Naohiro. / Cholesterol sulfate as a potential inhibitor of hepatitis C virus NS3 helicase. In: Journal of Enzyme Inhibition and Medicinal Chemistry. 2014 ; Vol. 29, No. 2. pp. 223-229.
    @article{ff02759a50934f4c87f3c18dcd8b876e,
    title = "Cholesterol sulfate as a potential inhibitor of hepatitis C virus NS3 helicase",
    abstract = "Hepatitis C virus nonstructural protein 3 (NS3) helicase is a promising target for developing new therapeutics. In this study, we identified cholesterol sulfate (CS) as a novel NS3 helicase inhibitor (IC50 = 1.7 ± 0.2 μM with a Hill coefficient of 3.9) by screening the extracts from marine organisms. The lack of the sulfate group, sterol structure or alkyl side chain of CS diminished the inhibition, suggesting that an anion binding and hydrophobic region in NS3 may be a target site of CS. It was further found that CS partly inhibits NS3-RNA binding activity, but exerted no or less inhibition against ATPase and serine protease activities. Moreover, we demonstrated that CS probably does not bind to RNA. Our findings suggest that CS may inhibit NS3 helicase not by abolishing the other NS3 activities but by inducing conformational changes via interaction with possible allosteric sites of NS3.",
    keywords = "Cholesterol sulfate, Hepatitis C virus, Marine organism, NS3 helicase",
    author = "Atsushi Furuta and Salam, {Kazi Abdus} and Nobuyoshi Akimitsu and Junichi Tanaka and Hidenori Tani and Atsuya Yamashita and Kohji Moriishi and Masamichi Nakakoshi and Masayoshi Tsubuki and Yuji Sekiguchi and Satoshi Tsuneda and Naohiro Noda",
    year = "2014",
    doi = "10.3109/14756366.2013.766607",
    language = "English",
    volume = "29",
    pages = "223--229",
    journal = "Journal of Enzyme Inhibition and Medicinal Chemistry",
    issn = "1475-6366",
    publisher = "Informa Healthcare",
    number = "2",

    }

    TY - JOUR

    T1 - Cholesterol sulfate as a potential inhibitor of hepatitis C virus NS3 helicase

    AU - Furuta, Atsushi

    AU - Salam, Kazi Abdus

    AU - Akimitsu, Nobuyoshi

    AU - Tanaka, Junichi

    AU - Tani, Hidenori

    AU - Yamashita, Atsuya

    AU - Moriishi, Kohji

    AU - Nakakoshi, Masamichi

    AU - Tsubuki, Masayoshi

    AU - Sekiguchi, Yuji

    AU - Tsuneda, Satoshi

    AU - Noda, Naohiro

    PY - 2014

    Y1 - 2014

    N2 - Hepatitis C virus nonstructural protein 3 (NS3) helicase is a promising target for developing new therapeutics. In this study, we identified cholesterol sulfate (CS) as a novel NS3 helicase inhibitor (IC50 = 1.7 ± 0.2 μM with a Hill coefficient of 3.9) by screening the extracts from marine organisms. The lack of the sulfate group, sterol structure or alkyl side chain of CS diminished the inhibition, suggesting that an anion binding and hydrophobic region in NS3 may be a target site of CS. It was further found that CS partly inhibits NS3-RNA binding activity, but exerted no or less inhibition against ATPase and serine protease activities. Moreover, we demonstrated that CS probably does not bind to RNA. Our findings suggest that CS may inhibit NS3 helicase not by abolishing the other NS3 activities but by inducing conformational changes via interaction with possible allosteric sites of NS3.

    AB - Hepatitis C virus nonstructural protein 3 (NS3) helicase is a promising target for developing new therapeutics. In this study, we identified cholesterol sulfate (CS) as a novel NS3 helicase inhibitor (IC50 = 1.7 ± 0.2 μM with a Hill coefficient of 3.9) by screening the extracts from marine organisms. The lack of the sulfate group, sterol structure or alkyl side chain of CS diminished the inhibition, suggesting that an anion binding and hydrophobic region in NS3 may be a target site of CS. It was further found that CS partly inhibits NS3-RNA binding activity, but exerted no or less inhibition against ATPase and serine protease activities. Moreover, we demonstrated that CS probably does not bind to RNA. Our findings suggest that CS may inhibit NS3 helicase not by abolishing the other NS3 activities but by inducing conformational changes via interaction with possible allosteric sites of NS3.

    KW - Cholesterol sulfate

    KW - Hepatitis C virus

    KW - Marine organism

    KW - NS3 helicase

    UR - http://www.scopus.com/inward/record.url?scp=84892899537&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84892899537&partnerID=8YFLogxK

    U2 - 10.3109/14756366.2013.766607

    DO - 10.3109/14756366.2013.766607

    M3 - Article

    VL - 29

    SP - 223

    EP - 229

    JO - Journal of Enzyme Inhibition and Medicinal Chemistry

    JF - Journal of Enzyme Inhibition and Medicinal Chemistry

    SN - 1475-6366

    IS - 2

    ER -