Inhibition of Hepatitis C Virus NS3 Helicase by Manoalide
Inhibition of Hepatitis C Virus NS3 Helicase by Manoalide
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DOI：
10.1021/np200883s
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发表时间：
2012-04-01
影响因子：
5.1
通讯作者：
Akimitsu, Nobuyoshi
中科院分区：
文献类型：
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作者：
Salam, Kazi Abdus;Furuta, Atsushi;Akimitsu, Nobuyoshi
丙型肝炎病毒（HCV）是世界上最流行的慢性传染病之一，丙型肝炎最终通过肝硬化发展为肝癌。HCV的NS 3蛋白具有核苷三磷酸酶（NTR）和RNA解旋酶活性。由于这两种活性对于病毒复制都是必不可少的，因此NS 3被提议作为抗病毒药物开发的理想靶点。在这项研究中，我们使用我们先前开发的高通量筛选光诱导电子转移（PET）系统，从海绵提取物中鉴定出了作为RNA解旋酶抑制剂的海藜芦内酯（1）。化合物1以剂量依赖性方式抑制NS 3的RNA解旋酶和ATP酶活性，IC 50值分别为15和70 μ M。生化动力学分析表明，1不影响表观K-m链RNA的表达，但1对表观K-m链RNA有抑制作用。单醛内酯（1）还具有抑制人DHX 36/RHAU（一种假定的RNA解旋酶）的ATP酶活性的能力。综上所述，我们得出结论，1通过靶向HCV NS 3和DHX 36/RHAU中保守的解旋酶核心结构域来抑制NS 3的ATP酶、RNA结合和解旋酶活性。
The hepatitis C virus (HCV) causes one of the most prevalent chronic infectious diseases in the world hepatitis C, which ultimately develops into liver cancer through cirrhosis. The NS3 protein of HCV possesses nucleoside triphosphatase (NTPase) and RNA helicase activities. As both activities are essential for viral replication, NS3 is proposed as an ideal target for antiviral drug development. In this study, we identified manoalide (1) from marine sponge extracts as an RNA helicase inhibitor using a high-throughput screening photoinduced electron transfer (PET) system that we previously developed. Compound 1 inhibits the RNA helicase and ATPase activities of NS3 in a dose dependent manner, with IC50 values of 15 and 70 mu M, respectively. Biochemical kinetic analysis demonstrated that 1 does not affect the apparent K-m stranded RNA was inhibited by 1. Monoalide (1) also has the ability to inhibit the ATPase activity of human DHX36/RHAU, a putative RNA helicase. Taken together, we conclude that 1 inhibits the ATPase, RNA binding, and helicase activities of NS3 by targeting the helicase core domain conserved in both HCV NS3 and DHX36/RHAU.