Identification of Hydroxyanthraquinones as Novel Inhibitors of Hepatitis C Virus NS3 Helicase

International Journal of Molecular Sciences

Atsushi Furuta¹  Masayoshi Tsubuki⁷  Miduki Endoh⁷  Tatsuki Miyamoto¹  Junichi Tanaka³  Kazi Abdus Salam⁵  Nobuyoshi Akimitsu⁵  Hidenori Tani⁴  Atsuya Yamashita⁸  Kohji Moriishi⁸  Masamichi Nakakoshi²  Yuji Sekiguchi⁶  Satoshi Tsuneda¹  Naohiro Noda¹ 

[1] Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan; E-Mails:;Department of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan; E-Mail:;Department of Chemistry, Biology and Marine Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan; E-Mail:;Environmental Measurement Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 16-1 Onogawa, Tsukuba, Ibaraki 305-8569, Japan; E-Mail:;Radioisotope Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; E-Mails:;Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan; E-Mail:;Institute of Medical Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan; E-Mails:;Department of Microbiology, Division of Medicine, Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan; E-Mails:

关键词: hepatitis C virus;    NS3 helicase;    fluorescence resonance energy transfer;    inhibitor;    hydroxyanthraquinone;    hypericin;    sennidin A;   

DOI  :  10.3390/ijms160818439

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.