Identification of hydroxyanthraquinones as novel inhibitors of hepatitis C Virus NS3 helicase

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

    Research output: Contribution to journalArticle

    9 Citations (Scopus)

    Abstract

    Hepatitis C virus (HCV) is an important etiological agent of severe liver diseases, including cirrhosis and hepatocellular carcinoma. The HCV genome encodes nonstructural protein 3 (NS3) helicase, which is a potential anti-HCV drug target because its enzymatic activity is essential for viral replication. Some anthracyclines are known to be NS3 helicase inhibitors and have a hydroxyanthraquinone moiety in their structures; mitoxantrone, a hydroxyanthraquinone analogue, is also known to inhibit NS3 helicase. Therefore, we hypothesized that the hydroxyanthraquinone moiety alone could also inhibit NS3 helicase. Here, we performed a structure–activity relationship study on a series of hydroxyanthraquinones by using a fluorescence-based helicase assay. Hydroxyanthraquinones inhibited NS3 helicase with IC<inf>50</inf> values in the micromolar range. The inhibitory activity varied depending on the number and position of the phenolic hydroxyl groups, and among different hydroxyanthraquinones examined, 1,4,5,8-tetrahydroxyanthraquinone strongly inhibited NS3 helicase with an IC<inf>50</inf> value of 6 μM. Furthermore, hypericin and sennidin A, which both have two hydroxyanthraquinone-like moieties, were found to exert even stronger inhibition with IC<inf>50</inf> values of 3 and 0.8 μM, respectively. These results indicate that the hydroxyanthraquinone moiety can inhibit NS3 helicase and suggest that several key chemical structures are important for the inhibition.

    Original languageEnglish
    Pages (from-to)18439-18453
    Number of pages15
    JournalInternational Journal of Molecular Sciences
    Volume16
    Issue number8
    DOIs
    Publication statusPublished - 2015 Aug 7

    Fingerprint

    hepatitis
    viruses
    Viruses
    Hepacivirus
    inhibitors
    proteins
    Proteins
    Inhibitory Concentration 50
    Mitoxantrone
    genome
    Anthracyclines
    liver
    Hydroxyl Radical
    Liver
    Liver Diseases
    Hepatocellular Carcinoma
    Assays
    drugs
    Fibrosis
    Genes

    Keywords

    • Fluorescence resonance energy transfer
    • Hepatitis C virus
    • Hydroxyanthraquinone
    • Hypericin
    • Inhibitor
    • NS3 helicase
    • Sennidin A

    ASJC Scopus subject areas

    • Physical and Theoretical Chemistry
    • Organic Chemistry
    • Spectroscopy
    • Inorganic Chemistry
    • Catalysis
    • Molecular Biology
    • Computer Science Applications

    Cite this

    Furuta, A., Tsubuki, M., Endoh, M., Miyamoto, T., Tanaka, J., Salam, K. A., ... Noda, N. (2015). Identification of hydroxyanthraquinones as novel inhibitors of hepatitis C Virus NS3 helicase. International Journal of Molecular Sciences, 16(8), 18439-18453. https://doi.org/10.3390/ijms160818439

    Identification of hydroxyanthraquinones as novel inhibitors of hepatitis C Virus NS3 helicase. / Furuta, Atsushi; Tsubuki, Masayoshi; Endoh, Miduki; Miyamoto, Tatsuki; Tanaka, Junichi; Salam, Kazi Abdus; Akimitsu, Nobuyoshi; Tani, Hidenori; Yamashita, Atsuya; Moriishi, Kohji; Nakakoshi, Masamichi; Sekiguchi, Yuji; Tsuneda, Satoshi; Noda, Naohiro.

    In: International Journal of Molecular Sciences, Vol. 16, No. 8, 07.08.2015, p. 18439-18453.

    Research output: Contribution to journalArticle

    Furuta, A, Tsubuki, M, Endoh, M, Miyamoto, T, Tanaka, J, Salam, KA, Akimitsu, N, Tani, H, Yamashita, A, Moriishi, K, Nakakoshi, M, Sekiguchi, Y, Tsuneda, S & Noda, N 2015, 'Identification of hydroxyanthraquinones as novel inhibitors of hepatitis C Virus NS3 helicase', International Journal of Molecular Sciences, vol. 16, no. 8, pp. 18439-18453. https://doi.org/10.3390/ijms160818439
    Furuta, Atsushi ; Tsubuki, Masayoshi ; Endoh, Miduki ; Miyamoto, Tatsuki ; Tanaka, Junichi ; Salam, Kazi Abdus ; Akimitsu, Nobuyoshi ; Tani, Hidenori ; Yamashita, Atsuya ; Moriishi, Kohji ; Nakakoshi, Masamichi ; Sekiguchi, Yuji ; Tsuneda, Satoshi ; Noda, Naohiro. / Identification of hydroxyanthraquinones as novel inhibitors of hepatitis C Virus NS3 helicase. In: International Journal of Molecular Sciences. 2015 ; Vol. 16, No. 8. pp. 18439-18453.
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    abstract = "Hepatitis C virus (HCV) is an important etiological agent of severe liver diseases, including cirrhosis and hepatocellular carcinoma. The HCV genome encodes nonstructural protein 3 (NS3) helicase, which is a potential anti-HCV drug target because its enzymatic activity is essential for viral replication. Some anthracyclines are known to be NS3 helicase inhibitors and have a hydroxyanthraquinone moiety in their structures; mitoxantrone, a hydroxyanthraquinone analogue, is also known to inhibit NS3 helicase. Therefore, we hypothesized that the hydroxyanthraquinone moiety alone could also inhibit NS3 helicase. Here, we performed a structure–activity relationship study on a series of hydroxyanthraquinones by using a fluorescence-based helicase assay. Hydroxyanthraquinones inhibited NS3 helicase with IC50 values in the micromolar range. The inhibitory activity varied depending on the number and position of the phenolic hydroxyl groups, and among different hydroxyanthraquinones examined, 1,4,5,8-tetrahydroxyanthraquinone strongly inhibited NS3 helicase with an IC50 value of 6 μM. Furthermore, hypericin and sennidin A, which both have two hydroxyanthraquinone-like moieties, were found to exert even stronger inhibition with IC50 values of 3 and 0.8 μM, respectively. These results indicate that the hydroxyanthraquinone moiety can inhibit NS3 helicase and suggest that several key chemical structures are important for the inhibition.",
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    AU - Furuta, Atsushi

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    AU - Tanaka, Junichi

    AU - Salam, Kazi Abdus

    AU - Akimitsu, Nobuyoshi

    AU - Tani, Hidenori

    AU - Yamashita, Atsuya

    AU - Moriishi, Kohji

    AU - Nakakoshi, Masamichi

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    AU - Tsuneda, Satoshi

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