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Biochemistry. 2018 Feb 13;57(6):907-911. doi: 10.1021/acs.biochem.7b01239. Epub 2018 Jan 19.

Design of a "Mini" Nucleic Acid Probe for Cooperative Binding of an RNA-Repeated Transcript Associated with Myotonic Dystrophy Type 1.

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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.


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 rCUGexp from the wild-type transcript and disrupt the rCUGexp-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.

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