Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules

Jessica L. Childs-Disney, Ewa Stepniak-Konieczna, Tuan Tran, Ilyas Yildirim, HaJeung Park, Catherine Z. Chen, Jason Hoskins, Noel Southall, Juan J. Marugan, Samarjit Patnaik, Wei Zheng, Chris P. Austin, George C. Schatz, Krzysztof Sobczak, Charles A. Thornton and Matthew D. Disney ()
Additional contact information
Jessica L. Childs-Disney: The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A1
Ewa Stepniak-Konieczna: Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University
Tuan Tran: The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A1
Ilyas Yildirim: Northwestern University, 2145 Sheridan Road
HaJeung Park: The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A1
Catherine Z. Chen: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health
Jason Hoskins: School of Medicine and Dentistry, University of Rochester
Noel Southall: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health
Juan J. Marugan: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health
Samarjit Patnaik: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health
Wei Zheng: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health
Chris P. Austin: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health
George C. Schatz: Northwestern University, 2145 Sheridan Road
Krzysztof Sobczak: Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University
Charles A. Thornton: School of Medicine and Dentistry, University of Rochester
Matthew D. Disney: The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A1

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3044

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