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 language | English |
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Pages (from-to) | 2455-2462 |
Number of pages | 8 |
Journal | ChemMedChem |
Volume | 9 |
Issue number | 11 |
DOIs | |
State | Published - 17 Aug 2014 |
Externally published | Yes |
Keywords
- DM2 therapeutics
- bisamidinium
- myotonic dystrophy
- triaminopyrimidine
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Pharmacology
- Drug Discovery
- General Pharmacology, Toxicology and Pharmaceutics
- Organic Chemistry