Coonrod Leslie A, Nakamori Masayuki, Wang Wenli, Carrell Samuel, Hilton Cameron L, Bodner Micah J, Siboni Ruth B, Docter Aaron G, Haley Michael M, Thornton Charles A, Berglund J Andrew
Institute of Molecular Biology and §Department of Chemistry and Biochemistry, University of Oregon , Eugene, Oregon 97403, United States.
ACS Chem Biol. 2013 Nov 15;8(11):2528-37. doi: 10.1021/cb400431f. Epub 2013 Sep 27.
Myotonic dystrophy (DM) is one of the most common forms of muscular dystrophy. DM is an autosomal dominant disease caused by a toxic gain of function RNA. The toxic RNA is produced from expanded noncoding CTG/CCTG repeats, and these CUG/CCUG repeats sequester the Muscleblind-like (MBNL) family of RNA binding proteins. The MBNL proteins are regulators of alternative splicing, and their sequestration has been linked with mis-splicing events in DM. A previously reported screen for small molecules found that pentamidine was able to improve splicing defects associated with DM. Biochemical experiments and cell and mouse model studies of the disease indicate that pentamidine and related compounds may work through binding the CTG*CAG repeat DNA to inhibit transcription. Analysis of a series of methylene linker analogues of pentamidine revealed that heptamidine reverses splicing defects and rescues myotonia in a DM1 mouse model.
强直性肌营养不良（DM）是最常见的肌营养不良形式之一。DM是一种由功能获得性毒性RNA引起的常染色体显性疾病。毒性RNA由扩展的非编码CTG/CCTG重复序列产生，这些CUG/CCUG重复序列隔离了肌肉失明样（MBNL）RNA结合蛋白家族。MBNL蛋白是可变剪接的调节因子，它们的隔离与DM中的错误剪接事件有关。先前报道的一项小分子筛选发现，喷他脒能够改善与DM相关的剪接缺陷。该疾病的生化实验以及细胞和小鼠模型研究表明，喷他脒及相关化合物可能通过结合CTG*CAG重复DNA来抑制转录。对喷他脒的一系列亚甲基连接体类似物的分析表明，庚脒可逆转DM1小鼠模型中的剪接缺陷并挽救肌强直。
