Rationally Designed Small Molecules Targeting the RNA That Causes Myotonic Dystrophy Type 1 Are Potently Bioactive
- 14 February 2012
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Chemical Biology
- Vol. 7 (5), 856-862
- https://doi.org/10.1021/cb200408a
Abstract
RNA is an important drug target, but it is difficult to design or discover small molecules that modulate RNA function. In the present study, we report that rationally designed, modularly assembled small molecules that bind the RNA that causes myotonic dystrophy type 1 (DM1) are potently bioactive in cell culture models. DM1 is caused when an expansion of r(CUG) repeats, or r(CUG)exp, is present in the 3′ untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA. r(CUG)exp folds into a hairpin with regularly repeating 5′CUG/3′GUC motifs and sequesters muscleblind-like 1 protein (MBNL1). A variety of defects are associated with DM1, including (i) formation of nuclear foci, (ii) decreased translation of DMPK mRNA due to its nuclear retention, and (iii) pre-mRNA splicing defects due to inactivation of MBNL1, which controls the alternative splicing of various pre-mRNAs. Previously, modularly assembled ligands targeting r(CUG)exp were designed using information in an RNA motif-ligand database. These studies showed that a bis-benzimidazole (H) binds the 5′CUG/3′GUC motif in r(CUG)exp. Therefore, we designed multivalent ligands to bind simultaneously multiple copies of this motif in r(CUG)exp. Herein, we report that the designed compounds improve DM1-associated defects including improvement of translational and pre-mRNA splicing defects and the disruption of nuclear foci. These studies may establish a foundation to exploit other RNA targets in genomic sequence.Keywords
This publication has 36 references indexed in Scilit:
- Expression of MBNL and CELF mRNA transcripts in muscles with myotonic dystrophyNeuromuscular Disorders, 2007
- High-Efficiency FLP and ΦC31 Site-Specific Recombination in Mammalian CellsPLOS ONE, 2007
- MicroRNAs and chromosomal abnormalities in cancer cellsOncogene, 2006
- Muscleblind-like protein 1 nuclear sequestration is a molecular pathology marker of DM1 and DM2.2006
- Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophyProceedings of the National Academy of Sciences of the United States of America, 2006
- Colocalization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophyJournal of Cell Science, 2005
- Woodchuck post‐transcriptional element induces nuclear export of myotonic dystrophy 3′ untranslated region transcriptsEMBO Reports, 2005
- RNA pathogenesis of the myotonic dystrophiesNeuromuscular Disorders, 2005
- Expansion and deletion of CTG repeats from human disease genes are determined by the direction of replication in E. coliNature Genetics, 1995
- Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues.The Journal of cell biology, 1995