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

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. Myotonic dystrophy type 1 (DM1) is caused by defects in the alternative splicing of pre-mRNA. Childs-Disney and colleagues report two small molecules that either induce or reverse DM1-associated splicing defects by modulating the binding of pre-mRNA to muscleblind-like 1 protein.