A Ligand That Targets CUG Trinucleotide Repeats
A Ligand That Targets CUG Trinucleotide Repeats
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DOI：
10.1002/chem.201602741
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发表时间：
2016-10-01
影响因子：
4.3
通讯作者：
Nakatani, Kazuhiko
中科院分区：
文献类型：
--
作者：
Li, Jinxing;Matsumoto, Jun;Nakatani, Kazuhiko
开发能够识别特定RNA二级和三级结构的小分子是目前开发调控基因表达和治疗药物的工具的重要研究课题。扩展的CUG三核苷酸重复序列，称为毒性RNA，捕获剪接因子MBNL 1，是神经系统疾病强直性肌营养不良1型（DM 1）的病因。本文介绍了与CUG三核苷酸重复序列结合的2，9-二氨基烷基取代的1，10-邻菲咯啉（DAP）的合理分子设计、合成和结合分析。熔解温度（Tm）分析、表面等离子体共振（SPR）分析和电喷雾飞行时间质谱（ESI-TOF）分析结果表明，DAP与r（CUG）（9）结合，但不与r（CAG）（9）和r（CGG）（9）结合。双荧光素酶测定清楚地表明DAP通过影响体外翻译而结合至r（CUG）（n）重复。
The development of small molecules that can recognize specific RNA secondary and tertiary structures is currently an important research topic for developing tools to modulate gene expression and therapeutic drugs. Expanded CUG trinucleotide repeats, known as toxic RNA, capture the splicing factor MBNL1 and are causative of neurological disorder myotonic dystrophy type 1 (DM1). Herein, the rational molecular design, synthesis, and binding analysis of 2,9-diaminoalkyl-substituted 1,10-phenanthroline (DAP), which bound to CUG trinucleotide repeats, is described. The results of melting temperature (T-m) analyses, surface plasmon resonance (SPR) assay, and electrospray spray ionization time-of-flight (ESI-TOF) mass spectrometry showed that DAP bound to r(CUG)(9) but not to r(CAG)(9) and r(CGG)(9). The dual luciferase assay clearly indicated DAP bound to the r(CUG)(n) repeat by affecting the translation in vitro.