Expanded RNA repeats cause more than 30 incurable diseases. One approach to mitigate their toxicity is by using small molecules that assemble into potent, oligomeric species upon binding to the disease-causing RNA in cells. Herein, we show that the expanded repeat [r(CUG)^exp] that causes myotonic dystrophy type 1 (DM1) catalyzes the in situ synthesis of its own inhibitor using an RNA-templated tetrazine ligation in DM1 patient-derived cells. The compound synthesized on-site improved DM1-associated defects at picomolar concentrations, enhancing potency by 10 000-fold, compared to its parent compounds that cannot undergo oligomerization. A fluorogenic reaction is also described where r(CUG)^exp templates the synthesis of its own imaging probe to enable visualization of the repeat in its native context in live cells and muscle tissue.

中文翻译：

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有毒RNA模板通过使用细胞和组织中的生物正交四氮嗪连接来合成其自身的荧光抑制剂。

扩增的RNA重复序列会导致30多种无法治愈的疾病。减轻其毒性的一种方法是使用小分子，这些小分子在与细胞中引起疾病​​的RNA结合后组装成有效的寡聚物种。本文中，我们显示了引起重张性营养不良1型（DM1）的扩增重复序列[r（CUG）^exp ]催化使用DM1患者来源的细胞中的RNA模板四嗪连接原位合成其自身的抑制剂。与不经历低聚反应的母体化合物相比，该化合物在皮摩尔浓度下现场合成的DM1相关缺陷得到改善，效价提高了10 000倍。还描述了一种荧光反应，其中r（CUG）^exp 模板将自己的成像探针合成，以使其在活细胞和肌肉组织中的天然背景下可视化重复。