Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
ACS Chem Biol. 2020 Jul 17;15(7):1820-1825. doi: 10.1021/acschembio.0c00417. Epub 2020 Jun 17.
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)] that causes myotonic dystrophy type 1 (DM1) catalyzes the 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) templates the synthesis of its own imaging probe to enable visualization of the repeat in its native context in live cells and muscle tissue.
扩展的 RNA 重复序列导致 30 多种无法治愈的疾病。一种减轻其毒性的方法是使用小分子，这些小分子在与细胞中致病的 RNA 结合时会组装成有效、寡聚的物质。在此，我们表明，导致肌萎缩性侧索硬化症 1 型（DM1）的扩展重复 [r(CUG)] 使用在 DM1 患者来源的细胞中基于 RNA 的四嗪连接催化其自身抑制剂的合成。在皮摩尔浓度下，在现场合成的化合物改善了与 DM1 相关的缺陷，与不能进行寡聚化的母体化合物相比，其效力提高了 10000 倍。还描述了一种荧光反应，其中 r(CUG) 模板合成其自身的成像探针，以能够在活细胞和肌肉组织中以其天然构象可视化重复。
