Small Molecules that Target the Toxic RNA in Myotonic Dystrophy Type 2

Lien Nguyen, Ju Yeon Lee, Chun Ho Wong, Steven C. Zimmerman

Research output: Contribution to journalArticle

Abstract

Myotonic dystrophy type 2 (DM2) is caused by an expansion of CCTG repeats in the zinc-finger protein gene (ZNF9). Transcribed CCUG repeats sequester muscleblind-like protein 1 (MBNL1), an important alternative splicing regulator, preventing its normal function, leading to the disease phenotype. We describe a series of ligands that disrupt the MBNL1-r(CCUG)n interaction as potential lead agents for developing DM2 therapeutics. A previously reported triaminopyrimidine-acridine conjugate was a moderate inhibitor in vitro, however it proved to be poorly water-soluble and not cell-permeable. To improve its therapeutic potential, the new set of ligands maintained the key triaminopyrimidine recognition unit but replaced the acridine intercalator with a bisamidinium groove binder. The optimized ligands exhibit low micromolar inhibition potency to MBNL1-r(CCUG)8. Importantly, the ligands are the first to show the ability to disrupt the MBNL1-r(CCUG)n foci in DM2 model cell culture and exhibit low cytotoxicity. Targeting toxic RNA: A series of optimized ligands with two triaminopyrimidine recognition units linked to a bisamidinium groove binder is described. They exhibit low-micromolar inhibition potency to the MBNL1-r(CCUG)8 interaction and are the first to show the ability to disrupt the MBNL1-r(CCUG)n foci in DM2 model cell culture and exhibit low cytotoxicity.

Original languageEnglish (US)
Pages (from-to)2455-2462
Number of pages8
JournalChemMedChem
Volume9
Issue number11
DOIs
StatePublished - Aug 17 2014

Keywords

  • DM2 therapeutics
  • bisamidinium
  • myotonic dystrophy
  • triaminopyrimidine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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