Abstract
Myotonic dystrophy type 1 (DM1) is caused by an expanded CUG repeat (CUGexp) that sequesters muscleblind-like 1 protein (MBNL1), a protein that regulates alternative splicing. CUGexp RNA is a validated drug target for this untreatable disease. Herein, we develop a bioactive small molecule that targets CUGexp RNA and is able to inhibit the CUGexp·MBNL1 interaction in cells that model DM1. The core of this small molecule is based on a ligand that was previously reported to be active in an in vitro assay. A derivative with a polyamine side chain was aqueous-soluble and cell penetrable. This ligand was able to disperse CUGexp ribonuclear foci and release MBNL1 from them as well as partially reversing the mis-splicing of the insulin receptor pre-mRNA in a DM1 cell model. Direct evidence for ribonuclear foci dispersion was obtained in live DM1 cell model using time-lapse confocal microscopy.
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