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A Novel CUGexp·MBNL1 Inhibitor with Therapeutic Potential for Myotonic Dystrophy Type 1
Author(s) -
Jahromi Amin Haghighat,
Zimmerman Steven C
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.975.7
Subject(s) - myotonic dystrophy , rna splicing , rna , small molecule , intron , microbiology and biotechnology , biology , chemistry , ligand (biochemistry) , alternative splicing , exon , biophysics , biochemistry , receptor , gene , genetics
Myotonic dystrophy type 1 (DM1) is caused by an expanded CUG repeat (CUG exp ) that sequesters muscleblind‐like 1 protein (MBNL1), a protein that regulates alternative splicing. CUG exp RNA is a validated drug target for this untreatable disease. Herein, we develop a bioactive small molecule that targets CUG exp RNA and is able to inhibit the CUG exp ·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 CUG exp 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.