Key result
Minor groove binder improves foci formation and pre-mRNA splicing defects in DM1 model cells.
Why the study?
DM1 is caused by a CTG-CAG repeat expansion producing toxic r(CUG)exp transcripts, requiring therapeutic agents targeting these nucleic acid structures.
A novel minor groove binder demonstrates potential as a lead compound for myotonic dystrophy type 1 by targeting specific nucleic acid repeats and improving pathological molecular features in vitro.
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.
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Li et al. (2021) studied Myotonic dystrophy type 1 (DM1). Small molecule with a thiazole peptidomimetic unit linked to two triaminotriazine recognition units was evaluated on Foci formation and pre-mRNA splicing defects in DM1 model cells. A rationally designed small molecule minor groove binder selectively targeted d(CTG)exp and r(CUG)exp to improve foci formation and pre-mRNA splicing defects in DM1 model cells.
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