Rocaglates, a class of natural compounds isolated from plants of the genus Aglaia, are potent inhibitors of translation initiation. They are proposed to form stacking interactions with polypurine sequences in the 5'-untranslated region (UTR) of selected mRNAs, thereby clamping the RNA substrate onto eIF4A and causing inhibition of the translation initiation complex. Since virus replication relies on the host translation machinery, it is not surprising that the rocaglate Silvestrol has broad-spectrum antiviral activity. Unfortunately, synthesis of Silvestrol is sophisticated and time-consuming, thus hampering the prospects for further antiviral drug development. Here, we present the less complex structured synthetic rocaglate CR-31-B (-) as a novel compound with potent broad-spectrum antiviral activity in primary cells and in an ex vivo bronchial epithelial cell system. CR-31-B (-) inhibited the replication of corona-, Zika-, Lassa-, Crimean Congo hemorrhagic fever viruses and, to a lesser extent, hepatitis E virus (HEV) at non-cytotoxic low nanomolar concentrations. Since HEV has a polypurine-free 5'-UTR that folds into a stable hairpin structure, we hypothesized that RNA clamping by Silvestrol and its derivatives may also occur in a polypurine-independent but structure-dependent manner. Interestingly, the HEV 5'-UTR conferred sensitivity towards Silvestrol but not to CR-31-B (-). However, if an exposed polypurine stretch was introduced into the HEV 5'-UTR, CR-31-B (-) became an active inhibitor comparable to Silvestrol. Moreover, thermodynamic destabilization of the HEV 5'-UTR led to reduced translational inhibition by Silvestrol, suggesting differences between rocaglates in their mode of action, most probably by engaging Silvestrol's additional dioxane moiety.

中文翻译：

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合成rocaglate CR-31-B（-）和eIF4A抑制剂Silvestrol的广谱抗病毒活性比较。

Rocaglates是从Aglaia属植物中分离出来的一类天然化合物，是有效的翻译起始抑制剂。提出它们与选定的mRNA的5'-非翻译区（UTR）中的多嘌呤序列形成堆积相互作用，从而将RNA底物夹在eIF4A上并引起翻译起始复合物的抑制。由于病毒复制依赖于宿主翻译机制，因此草酸盐Silvestrol具有广谱抗病毒活性也就不足为奇了。不幸的是，Silvestrol的合成非常复杂且费时，因此阻碍了进一步开发抗病毒药物的前景。这里，我们目前提出的结构较简单的合成rocaglate CR-31-B（-）作为一种新型化合物，在原代细胞和离体支气管上皮细胞系统中具有有效的广谱抗病毒活性。CR-31-B（-）在无细胞毒性的低纳摩尔浓度下，抑制了日冕，寨卡，拉萨，克里米亚刚果出血热病毒的复制，并在较小程度上抑制了戊型肝炎病毒（HEV）的复制。由于HEV具有折叠成稳定发夹结构的无聚嘌呤的5'-UTR，因此我们假设Silvestrol及其衍生物的RNA夹持也可能以与聚嘌呤无关但与结构有关的方式发生。有趣的是，HEV 5'-UTR赋予了对Silvestrol的敏感性，而不是对CR-31-B（-）的敏感性。但是，如果将暴露的聚嘌呤段引入HEV 5'-UTR，CR-31-B（-）成为与Silvestrol相当的活性抑制剂。此外，HEV 5'-UTR的热力学不稳定导致Silvestrol的翻译抑制作用降低，这表明rocaglates在作用方式上的差异，很可能是通过Silvestrol的其他二恶烷部分参与的。