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A Novel Minor Groove Binder as a Potential Therapeutic Agent for Myotonic Dystrophy Type 1.

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.

SUBMITTER: Li K

PROVIDER: S-EPMC8429064 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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A Novel Minor Groove Binder as a Potential Therapeutic Agent for Myotonic Dystrophy Type 1.

Li Ke K Krueger Sarah B SB Zimmerman Steven C SC

ChemMedChem 20210610 17

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)<sup>exp</sup> , 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 pept ...[more]

PMID: 34114350

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