@article{3bb0748c482742e4844066525dcebc4c,
title = "Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules",
abstract = "The ability to control pre-mRNA splicing with small molecules could facilitate the development of therapeutics or cell-based circuits that control gene function. Myotonic dystrophy type 1 is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1 protein (MBNL1) by expanded, non-coding r(CUG) repeats (r(CUG)exp). Here we report two small molecules that induce or ameliorate alternative splicing dysregulation. A thiophene-containing small molecule (1) inhibits the interaction of MBNL1 with its natural pre-mRNA substrates. Compound (2), a substituted naphthyridine, binds r(CUG)exp and displaces MBNL1. Structural models show that 1 binds MBNL1 in the Zn-finger domain and that 2 interacts with UU loops in r(CUG)exp. This study provides a structural framework for small molecules that target MBNL1 by mimicking r(CUG)exp and shows that targeting MBNL1 causes dysregulation of alternative splicing, suggesting that MBNL1 is thus not a suitable therapeutic target for the treatment of myotonic dystrophy type 1.",
author = "Childs-Disney, {Jessica L.} and Ewa Stepniak-Konieczna and Tuan Tran and Ilyas Yildirim and Park, {Ha Jeung} and Chen, {Catherine Z.} and Jason Hoskins and Noel Southall and Marugan, {Juan J.} and Samarjit Patnaik and Wei Zheng and Austin, {Chris P.} and Schatz, {George C.} and Krzysztof Sobczak and Thornton, {Charles A.} and Disney, {Matthew D.}",
note = "Funding Information: We thank Don Mackenzie from the Marigold Foundation for his support of this research project in particular and DM1 research in general and Amit Kumar for preliminary studies; and Professor Glenn E. Morris (Wolfson Centre for Inherited Neuromuscular Disease) for generously providing the MB1a antibody (anti-MBNL1). Funding for this work was provided by the Scripps Research Institute, the Muscular Dystrophy Association (158552 to MDD), the National Institutes of Health (3R01GM079235-02S1 and 1R01GM079235-01A2 to MDD; AR049077 and U54NS48843 to CAT), the Molecular Libraries Initiative of the NIH Roadmap for Medical Research, the Marigold Foundation postdoctoral fellowship, the PS-OC Center of the NIH/NCI (grant 1U54CA143869-01; I.Y. and G.C.S.), and the Foundation for Polish Science—TEAM programme co-financed by the European Union within the European Regional Development Fund (E.S-K and K.S.).",
year = "2013",
month = jun,
day = "28",
doi = "10.1038/ncomms3044",
language = "English",
volume = "4",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}