1,3-二氨基异喹啉衍生物的二聚体形式挽救了肌强直性营养不良 1 型小鼠模型中 Atp2a1 和 Clcn1 基因的剪接错误。
The Dimeric Form of 1,3-Diaminoisoquinoline Derivative Rescued the Mis-splicing of Atp2a1 and Clcn1 Genes in Myotonic Dystrophy Type 1 Mouse Model.
机构信息
Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, 567-0047, Japan.
Department of Neurology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan.
出版信息
Chemistry. 2020 Nov 11;26(63):14305-14309. doi: 10.1002/chem.202001572. Epub 2020 Oct 6.
Expanded CUG repeat RNA in the dystrophia myotonia protein kinase (DMPK) gene causes myotonic dystrophy type 1 (DM1) and sequesters RNA processing proteins, such as the splicing factor muscleblind-like 1 protein (MBNL1). Sequestration of splicing factors results in the mis-splicing of some pre-mRNAs. Small molecules that rescue the mis-splicing in the DM1 cells have drawn attention as potential drugs to treat DM1. Herein we report a new molecule JM642 consisted of two 1,3-diaminoisoquinoline chromophores having an auxiliary aromatic unit at the C5 position. JM642 alternates the splicing pattern of the pre-mRNA of the Ldb3 gene in the DM1 cell model and Clcn1 and Atp2a1 genes in the DM1 mouse model. In vitro binding analysis by surface plasmon resonance (SPR) assay to the r(CUG) repeat and disruption of ribonuclear foci in the DM1 cell model suggested the binding of JM642 to the expanded r(CUG) repeat in vivo, eventually rescue the mis-splicing.
在肌强直性营养不良蛋白激酶 (DMPK) 基因中的扩展 CUG 重复 RNA 导致 1 型肌强直性营养不良 (DM1)，并隔离 RNA 处理蛋白，如剪接因子肌肉盲样蛋白 1 蛋白 (MBNL1)。剪接因子的隔离导致一些前体 mRNA 的错误剪接。能够挽救 DM1 细胞中错误剪接的小分子已引起人们对治疗 DM1 的潜在药物的关注。在此，我们报告了一种新的分子 JM642，它由两个 1,3-二氨基异喹啉发色团组成，在 C5 位置具有辅助芳香单元。JM642 改变了 DM1 细胞模型中 Ldb3 基因、DM1 小鼠模型中 Clcn1 和 Atp2a1 基因的前体 mRNA 的剪接模式。通过表面等离子体共振 (SPR) 分析与 r(CUG) 重复的体外结合以及 DM1 细胞模型中核糖核蛋白焦点的破坏表明，JM642 在体内与扩展的 r(CUG) 重复结合，最终挽救了错误剪接。
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