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

Ke Li, Sarah B. Krueger, Steven C. Zimmerman

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2638-2644
Number of pages7
JournalChemMedChem
Volume16
Issue number17
DOIs
StatePublished - Sep 6 2021

Keywords

  • DNA/RNA recognition
  • minor groove binders
  • myotonic dystrophy
  • thiazole
  • triaminotriazine

ASJC Scopus subject areas

  • Drug Discovery
  • General Pharmacology, Toxicology and Pharmaceutics
  • Molecular Medicine
  • Biochemistry
  • Pharmacology
  • Organic Chemistry

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