A novel CUGexp·MBNL1 inhibitor with therapeutic potential for myotonic dystrophy type 1

Amin Haghighat Jahromi, Lien Nguyen, Yuan Fu, Kali A. Miller, Anne M. Baranger, Steven C. Zimmerman

Research output: Contribution to journalArticle


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 currently untreatable disease. Herein, we develop a bioactive small molecule (1) 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 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 CUGexp 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.

Original languageEnglish (US)
Pages (from-to)1037-1043
Number of pages7
JournalACS chemical biology
Issue number5
StatePublished - May 17 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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