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DDX3 inhibitors show antiviral activity against positive-sense single-stranded RNA viruses but not against negative-sense single-stranded RNA viruses: The coxsackie B model.
Antiviral Research ( IF 4.5 ) Pub Date : 2020-03-20 , DOI: 10.1016/j.antiviral.2020.104750 Paola Quaranta 1 , Giulia Lottini 1 , Giulia Chesi 1 , Flavia Contrafatto 1 , Roberta Russotto 1 , Lisa Macera 1 , Michele Lai 1 , Pietro Giorgio Spezia 1 , Annalaura Brai 2 , Maurizio Botta 3 , Giulia Freer 1 , Mauro Pistello 4
Antiviral Research ( IF 4.5 ) Pub Date : 2020-03-20 , DOI: 10.1016/j.antiviral.2020.104750 Paola Quaranta 1 , Giulia Lottini 1 , Giulia Chesi 1 , Flavia Contrafatto 1 , Roberta Russotto 1 , Lisa Macera 1 , Michele Lai 1 , Pietro Giorgio Spezia 1 , Annalaura Brai 2 , Maurizio Botta 3 , Giulia Freer 1 , Mauro Pistello 4
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Picornaviridae are positive-sense single stranded RNA viruses with a similar genomic structure lacking a cap at the 5' end, but with a highly structured 5'-untranslated region (UTR) containing an internal ribosome entry site (IRES). IRES allows ribosomes to be recruited by the viral RNA and initiate translation in a cap-independent manner. Coxsackie virus type B (CV-B) belong to Picornaviridae and are widespread in human population. They usually cause subclinical infections but, occasionally, also severe diseases with various clinical manifestations. CV-B have no specific therapy. DEAD-box polypeptide 3 (DDX3) is a member of the Asp-Glu-Ala-Asp (DEAD)-box family with an ATP-dependent RNA unwinding helicase activity. Recently, several positive-sense single strand RNA viruses have been shown to need DDX3 for their translation. Here, we show that several DDX3 inhibitors reduced CV-B replication and production of viral protein, particularly when added within 12 h of infection. Based on in vitro and in silico data, we hypothesized that DDX3 inhibitors hamper interaction between DDX3 and viral IRES in a stereodynamic fashion. Accordingly, the DDX3 inhibitors tested have no activity against the Vesicular Stomatitis virus and Measles virus, which are negative-sense single stranded RNA viruses and use cap-dependent translation. This study suggests that DDX3 is required by RNA viruses lacking a cap and show that this enzyme is a valuable target to design antiviral molecules against CV-B. Thus, DDX3 is dispensable for cap-dependent translation, but required for translation of transcripts containing secondary structure in their UTRs.
中文翻译：
DDX3抑制剂显示对正义单链RNA病毒具有抗病毒活性，但对负义单链RNA病毒没有抗病毒活性：柯萨奇B模型。
Picornaviridae是具有相似基因组结构的正义单链RNA病毒，在5'端没有帽，但是具有高度结构化的5'非翻译区（UTR），其中包含内部核糖体进入位点（IRES）。IRES允许核糖体被病毒RNA募集并以不依赖帽的方式启动翻译。柯萨奇病毒B型（CV-B）属于Picornaviridae，并在人类中广泛分布。它们通常引起亚临床感染，但偶尔也引起具有各种临床表现的严重疾病。CV-B没有特异性疗法。DEAD盒多肽3（DDX3）是具有ATP依赖性RNA解旋解旋酶活性的Asp-Glu-Ala-Asp（DEAD）盒家族的成员。最近，已显示几种正义单链RNA病毒需要DDX3进行翻译。这里，我们显示了几种DDX3抑制剂可降低CV-B复制和病毒蛋白的产生，尤其是在感染后12小时内添加时。根据体外和计算机模拟数据，我们假设DDX3抑制剂以立体动力学方式阻碍了DDX3和病毒IRES之间的相互作用。因此，所测试的DDX3抑制剂对水泡性口腔炎病毒和麻疹病毒没有活性，所述水疱性口腔炎病毒和麻疹病毒是负义单链RNA病毒并且使用帽依赖性翻译。这项研究表明，缺乏顶盖的RNA病毒需要DDX3，并且表明该酶是设计针对CV-B的抗病毒分子的重要靶标。因此，DDX3对于依赖于帽的翻译是必不可少的，但是对于翻译其UTR中包含二级结构的转录本则是必需的。
更新日期：2020-03-21
中文翻译：
DDX3抑制剂显示对正义单链RNA病毒具有抗病毒活性，但对负义单链RNA病毒没有抗病毒活性：柯萨奇B模型。
Picornaviridae是具有相似基因组结构的正义单链RNA病毒，在5'端没有帽，但是具有高度结构化的5'非翻译区（UTR），其中包含内部核糖体进入位点（IRES）。IRES允许核糖体被病毒RNA募集并以不依赖帽的方式启动翻译。柯萨奇病毒B型（CV-B）属于Picornaviridae，并在人类中广泛分布。它们通常引起亚临床感染，但偶尔也引起具有各种临床表现的严重疾病。CV-B没有特异性疗法。DEAD盒多肽3（DDX3）是具有ATP依赖性RNA解旋解旋酶活性的Asp-Glu-Ala-Asp（DEAD）盒家族的成员。最近，已显示几种正义单链RNA病毒需要DDX3进行翻译。这里，我们显示了几种DDX3抑制剂可降低CV-B复制和病毒蛋白的产生，尤其是在感染后12小时内添加时。根据体外和计算机模拟数据，我们假设DDX3抑制剂以立体动力学方式阻碍了DDX3和病毒IRES之间的相互作用。因此，所测试的DDX3抑制剂对水泡性口腔炎病毒和麻疹病毒没有活性，所述水疱性口腔炎病毒和麻疹病毒是负义单链RNA病毒并且使用帽依赖性翻译。这项研究表明，缺乏顶盖的RNA病毒需要DDX3，并且表明该酶是设计针对CV-B的抗病毒分子的重要靶标。因此，DDX3对于依赖于帽的翻译是必不可少的，但是对于翻译其UTR中包含二级结构的转录本则是必需的。
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