Inhibition of both protease and helicase activities of hepatitis C virus NS3 by an ethyl acetate extract of marine sponge Amphimedon sp.
Inhibition of both protease and helicase activities of hepatitis C virus NS3 by an ethyl acetate extract of marine sponge Amphimedon sp.
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DOI：
10.1371/journal.pone.0048685
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Moriishi K
中科院分区：
文献类型：
--
作者：
Fujimoto Y;Salam KA;Furuta A;Matsuda Y;Fujita O;Tani H;Ikeda M;Kato N;Sakamoto N;Maekawa S;Enomoto N;de Voogd NJ;Nakakoshi M;Tsubuki M;Sekiguchi Y;Tsuneda S;Akimitsu N;Noda N;Yamashita A;Tanaka J;Moriishi K
利巴韦林、干扰素和病毒蛋白酶抑制剂的联合治疗有望在丙型肝炎病毒（HCV）感染患者中引起高水平的持续病毒学应答。然而，在临床试验中遇到了这种联合治疗的几种严重副作用。为了开发更有效和更安全的抗HCV化合物，我们使用来自几种HCV株的复制子系统来筛选来自日本冲绳县周围海域的54种生物的84种提取物。从海洋海绵Amphimedon sp.制备的乙酸乙酯可溶性提取物对病毒复制的抑制作用最高，在来自基因型1b和2a的亚基因组复制子细胞系中的EC 50值分别为1.5和24.9 µg/ml。但提取物对干扰素诱导的信号传导或细胞毒性没有影响。在JFH 1-Huh 7细胞培养系统中，相对于对照，用提取物处理抑制了30%的病毒产生。体外酶学测定显示，用提取物处理抑制了NS 3的解旋酶和蛋白酶活性，IC 50值分别为18.9和10.9 μg/ml。用双齿藻提取物处理抑制RNA结合能力，但不抑制ATP酶活性。这些结果表明，包括在双链藻属物种中的新化合物可以靶向HCV NS 3的蛋白酶和解旋酶活性。
Combination therapy with ribavirin, interferon, and viral protease inhibitors could be expected to elicit a high level of sustained virologic response in patients infected with hepatitis C virus (HCV). However, several severe side effects of this combination therapy have been encountered in clinical trials. In order to develop more effective and safer anti-HCV compounds, we employed the replicon systems derived from several strains of HCV to screen 84 extracts from 54 organisms that were gathered from the sea surrounding Okinawa Prefecture, Japan. The ethyl acetate-soluble extract that was prepared from marine sponge Amphimedon sp. showed the highest inhibitory effect on viral replication, with EC50 values of 1.5 and 24.9 µg/ml in sub-genomic replicon cell lines derived from genotypes 1b and 2a, respectively. But the extract had no effect on interferon-inducing signaling or cytotoxicity. Treatment with the extract inhibited virus production by 30% relative to the control in the JFH1-Huh7 cell culture system. The in vitro enzymological assays revealed that treatment with the extract suppressed both helicase and protease activities of NS3 with IC50 values of 18.9 and 10.9 µg/ml, respectively. Treatment with the extract of Amphimedon sp. inhibited RNA-binding ability but not ATPase activity. These results suggest that the novel compound(s) included in Amphimedon sp. can target the protease and helicase activities of HCV NS3.
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影响因子：
5.4
作者：
FAILLA, C;TOMEI, L;DEFRANCESCO, R
通讯作者：
DEFRANCESCO, R
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影响因子：
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作者：
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通讯作者：
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影响因子：
5.4
作者：
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通讯作者：
De Francesco, R