title: A novel CUG(exp)·MBNL1 inhibitor with therapeutic potential for myotonic dystrophy type 1.
abstract: 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 currently untreatable disease. Herein, we develop a bioactive small molecule (1) 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 ligand 2, which was previously reported to be active in an in vitro assay. A polyamine-derivative side chain was conjugated to this core to make it aqueous-soluble and cell-penetrable. In a DM1 cell model this conjugate was found to disperse CUG(exp) ribonuclear foci, release MBNL1, and partially reverse the mis-splicing of the insulin receptor pre-mRNA. Direct evidence for ribonuclear foci dispersion by this ligand was obtained in a live DM1 cell model using time-lapse confocal microscopy.
authors.affiliation: Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL, USA.
authors.forename: Amin Haghighat
authors.initials: AH
authors.lastname: Jahromi
authors.forename: Lien
authors.initials: L
authors.lastname: Nguyen
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fu
authors.forename: Kali A
authors.initials: KA
authors.lastname: Miller
authors.forename: Anne M
authors.initials: AM
authors.lastname: Baranger
authors.forename: Steven C
authors.initials: SC
authors.lastname: Zimmerman
mesh_terms: D001483:Base Sequence; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D008024:Ligands; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009223:Myotonic Dystrophy / Q000188:drug therapy*; D011073:Polyamines / Q000737:chemistry; D012322:RNA Precursors / Q000378:metabolism; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects*
chemical_list: D008024:Ligands; C493663:MBNL1 protein, human; D011073:Polyamines; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D011972:Receptor, Insulin