title: Small molecules that target the toxic RNA in myotonic dystrophy type 2.
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.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave., Urbana, IL 61801 (USA).
authors.forename: Lien
authors.initials: L
authors.lastname: Nguyen
authors.forename: JuYeon
authors.initials: J
authors.lastname: Lee
authors.forename: Chun-Ho
authors.initials: CH
authors.lastname: Wong
authors.forename: Steven C
authors.initials: SC
authors.lastname: Zimmerman
mesh_terms: D000166:Acridines / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D007700:Kinetics; D008024:Ligands; D018895:Microsatellite Repeats; D018613:Microscopy, Confocal; D009223:Myotonic Dystrophy / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000737:chemistry; D012313:RNA / Q000737:chemistry* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000166:Acridines; D007093:Imidazoles; D007364:Intercalating Agents; D008024:Ligands; C493663:MBNL1 protein, human; D011743:Pyrimidines; D016601:RNA-Binding Proteins; C535204:bisamidinium; D012313:RNA; C030986:pyrimidine
keywords: DM2 therapeutics; bisamidinium; myotonic dystrophy; triaminopyrimidine