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首页> 外文期刊>The FEBS journal >Hairpin ribozymes in combination with siRNAs against highly conserved hepatitis C virus sequence inhibit RNA replication and protein translation from hepatitis C virus subgenomic replicons
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Hairpin ribozymes in combination with siRNAs against highly conserved hepatitis C virus sequence inhibit RNA replication and protein translation from hepatitis C virus subgenomic replicons

机译：发夹状核酶与针对高度保守的丙型肝炎病毒序列的siRNA结合可抑制丙型肝炎病毒亚基因组复制子的RNA复制和蛋白质翻译

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摘要

Chronic hepatitis C virus (HCV) infection is a clinically important liver disease with limited therapeutic options in a significant proportion of patients. Therefore, novel efficient therapeutic agents are needed. Because the 5'- and 3'-untranslated regions (UTRs) of HCV are highly conserved and functionally important for HCV replication, they are attractive targets for RNA-cleaving ribozymes or small interfering RNAs (siRNAs). In this study hairpin ribozymes (Rz) targeting HCV 5'- and 3'-UTR sequences were expressed from a retroviral vector transcript under control of two different RNA polIII promoters (tRNA(Val), U6). Ribozymes were evaluated in monocistronic, subgenomic I389/hyg-ubi/NS3-3'/5.1 HCV replicon cells as single agents or in combination with siRNAs against HCV 5'- or 3'-UTR recently demonstrated to inhibit HCV replicons. Additionally, ribozyme constructs were generated with the 3'-terminus of the ribozyme flanked by constitutive transport element (CTE) sequences, an RNA motif that has previously been shown to enhance cleavage activity of hammerhead ribozymes. In our study, tRNA(Val) as well as U6 promoter-driven Rzs markedly reduced HCV replicon RNA expression and HCV internal ribosome entry site (IRES)-mediated HCV NS5B protein translation from monocistronic subgenomic replicons. However, attachment of CTE sequences to the 3'-terminus did not significantly enhance activity of Rzs tested in this study. Interestingly, we detected additive HCV inhibitory effects for combinations of tRNA(Val)-driven Rzs and U6-derived siRNAs both directed against highly conserved 5'- and 3'-UTR sequence, suggesting that a dual strategy of ribozymes and siRNAs might become a powerful molecular tool to specifically silence HCV RNA replication.
机译：慢性丙型肝炎病毒（HCV）感染是临床上重要的肝病，在很大比例的患者中治疗选择有限。因此，需要新型有效的治疗剂。由于HCV的5'和3'非翻译区（UTR）高度保守并且在功能上对于HCV复制很重要，因此它们是RNA裂解核酶或小干扰RNA（siRNA）的诱人靶标。在这项研究中，靶向HCV 5'-和3'-UTR序列的发夹状核酶（Rz）在两个不同的RNA polIII启动子（tRNA（Val），U6）的控制下从逆转录病毒载体转录物中表达出来。在单顺反子，亚基因组I389 / hyg-ubi / NS3-3'/ 5.1 HCV复制子细胞中评估了核酶，作为单药或与针对HCV 5'-或3'-UTR的siRNA组合使用，最近证实可抑制HCV复制子。另外，产生了核酶构建体，其核酶的3'末端侧接组成性转运元件（CTE）序列，RNA是先前已显示出可增强锤头状核酶的裂解活性的RNA基序。在我们的研究中，tRNA（Val）以及U6启动子驱动的Rzs显着降低了HCV复制子RNA的表达和HCV内部核糖体进入位点（IRES）介导的单顺反子亚基因组复制子的HCV NS5B蛋白翻译。但是，将CTE序列连接到3'端并没有显着增强本研究中测试的Rzs的活性。有趣的是，我们检测到针对高度保守的5'-和3'-UTR序列的tRNA（Val）驱动的Rzs和U6衍生的siRNA组合的加性HCV抑制作用，这表明核酶和siRNA的双重策略可能成为一种强大的分子工具，可专门沉默HCV RNA复制。

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