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
Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.
Radioisotope Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Mar Drugs. 2014 Jan 21;12(1):462-76. doi: 10.3390/md12010462.
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.
丙型肝炎病毒（HCV）是导致慢性肝炎、肝硬化和肝细胞癌的重要病原体。HCV非结构蛋白3（NS3）解旋酶因其在病毒复制中的关键作用，是新型药物开发的一个潜在靶点。在本研究中，我们通过筛选海洋生物提取物，从一种海洋海绵中鉴定出了卤硫酸3（hal3）和苏瓦宁为新型NS3解旋酶抑制剂，其IC50值分别为4 μM和3 μM。hal3和苏瓦宁均能抑制NS3解旋酶的ATP酶、RNA结合和丝氨酸蛋白酶活性，IC50值分别为8 μM、8 μM和14 μM，以及7 μM、3 μM和34 μM。然而，与HCV NS3解旋酶共享催化核心（主要由ATP酶和RNA结合位点组成）的登革热病毒（DENV）NS3解旋酶，即使在100 μM的浓度下也不受hal3和苏瓦宁的抑制。因此，我们得出结论，hal3和苏瓦宁通过与NS3中的变构位点相互作用，而非与催化核心结合，特异性抑制HCV NS3解旋酶。这可能通过诱导构象变化导致了所有NS3活性的抑制。
