Enterovirus 71 (EV71) poses serious threats to human health, particularly in Southeast Asia, and no drugs or vaccines are available. Previous work identified the stem loop II structure of the EV71 internal ribosomal entry site as vital to viral translation and a potential target. After screening an RNA-biased library using a peptide-displacement assay, we identify DMA-135 as a dose-dependent inhibitor of viral translation and replication with no significant toxicity in cell-based studies. Structural, biophysical, and biochemical characterization support an allosteric mechanism in which DMA-135 induces a conformational change in the RNA structure that stabilizes a ternary complex with the AUF1 protein, thus repressing translation. This mechanism is supported by pull-down experiments in cell culture. These detailed studies establish enterovirus RNA structures as promising drug targets while revealing an approach and mechanism of action that should be broadly applicable to functional RNA targeting.

肠道病毒 71 (EV71) 对人类健康构成严重威胁，特别是在东南亚，并且没有可用的药物或疫苗。先前的工作确定了 EV71 内部核糖体进入位点的茎环 II 结构对病毒翻译和潜在目标至关重要。在使用肽置换试验筛选偏向 RNA 的文库后，我们将 DMA-135 鉴定为病毒翻译和复制的剂量依赖性抑制剂，在基于细胞的研究中没有显着毒性。结构、生物物理和生化表征支持变构机制，其中 DMA-135 诱导 RNA 结构的构象变化，稳定与 AUF1 蛋白的三元复合物，从而抑制翻译。这种机制得到了细胞培养中下拉实验的支持。