Hsieh Wei-Che, Bahal Raman, Thadke Shivaji A, Bhatt Kirti, Sobczak Krzysztof, Thornton Charles, Ly Danith H
Department of Chemistry, ‡Institute for Biomolecular Design and Discovery (IBD), and §CNAST, Carnegie Mellon University , 4400 Fifth Avenue, Pittsburgh, Pennsylvania 15213, United States.
Department of Neurology, Box 645, University of Rochester Medical Center , 601 Elmwood Avenue, Rochester, New York 14642, United States.
Biochemistry. 2018 Feb 13;57(6):907-911. doi: 10.1021/acs.biochem.7b01239. Epub 2018 Jan 19.
Toxic RNAs containing expanded trinucleotide repeats are the cause of many neuromuscular disorders, one being myotonic dystrophy type 1 (DM1). DM1 is triggered by CTG-repeat expansion in the 3'-untranslated region of the DMPK gene, resulting in a toxic gain of RNA function through sequestration of MBNL1 protein, among others. Herein, we report the development of a relatively short miniPEG-γ peptide nucleic acid probe, two triplet repeats in length, containing terminal pyrene moieties, that is capable of binding rCUG repeats in a sequence-specific and selective manner. The newly designed probe can discriminate the pathogenic rCUG from the wild-type transcript and disrupt the rCUG-MBNL1 complex. The work provides a proof of concept for the development of relatively short nucleic acid probes for targeting RNA-repeat expansions associated with DM1 and other related neuromuscular disorders.
含有扩展三核苷酸重复序列的毒性RNA是许多神经肌肉疾病的病因，其中之一是1型强直性肌营养不良症（DM1）。DM1由DMPK基因3'-非翻译区的CTG重复序列扩增引发，导致RNA功能毒性增加，其中包括通过隔离MBNL1蛋白。在此，我们报告了一种相对较短的miniPEG-γ肽核酸探针的研发，其长度为两个三联体重复序列，含有末端芘基团，能够以序列特异性和选择性方式结合rCUG重复序列。新设计的探针可以区分致病性rCUG与野生型转录本，并破坏rCUG-MBNL1复合物。这项工作为开发针对与DM1及其他相关神经肌肉疾病相关的RNA重复序列扩增的相对较短核酸探针提供了概念验证。
