Abstract
Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder that is inherited in an autosomal dominant manner. DM1 originates in a (CTG⋅CAG) repeat expansion in the 3'-UTR of the dystrophia myotonic protein kinase (DMPK) gene on chromosome 19. One of the transcripts, r(CUG)(exp) , is toxic in various ways. Herein we report a rationally designed small molecule with a thiazole peptidomimetic unit that can serve as a minor groove binder for the nucleic acid targets. This peptide unit linked to two triaminotriazine recognition units selectively binds to d(CTG)(exp) to inhibit the transcription process, and also targets r(CUG)(exp) selectively to improve representative DM1 pathological molecular features, including foci formation and pre-mRNA splicing defects in DM1 model cells. As such, it represents a new structure type that might serve as a lead compound for future structure-activity optimization.