title: A Potent Inhibitor of Protein Sequestration by Expanded Triplet (CUG) Repeats that Shows Phenotypic Improvements in a Drosophila Model of Myotonic Dystrophy.
abstract: Myotonic dystrophy is the most common form of adult-onset muscular dystrophy, originating in a CTG repeat expansion in the DMPK gene. The expanded CUG transcript sequesters MBNL1, a key regulator of alternative splicing, leading to the misregulation of numerous pre-mRNAs. We report an RNA-targeted agent as a possible lead compound for the treatment of myotonic dystrophy type 1 (DM1) that reveals both the promise and challenges for this type of small-molecule approach. The agent is a potent inhibitor of the MBNL1-rCUG complex with an inhibition constant (Ki ) of 25±8 nm, and is also relatively nontoxic to HeLa cells, able to dissolve nuclear foci, and correct the insulin receptor splicing defect in DM1 model cells. Moreover, treatment with this compound improves two separate disease phenotypes in a Drosophila model of DM1: adult external eye degeneration and larval crawling defect. However, the compound has a relatively low maximum tolerated dose in mice, and its cell uptake may be limited, providing insight into directions for future development.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave., Urbana, IL, 61801, USA.
authors.forename: Long M
authors.initials: LM
authors.lastname: Luu
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.affiliation: Laboratory of Drosophila Research and School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, P.R. China.
authors.forename: Shaohong
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave., Urbana, IL, 61801, USA.
authors.forename: JuYeon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave., Urbana, IL, 61801, USA.
authors.forename: Hyang Yeon
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave., Urbana, IL, 61801, USA.
authors.forename: Chun-Ho
authors.initials: CH
authors.lastname: Wong
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave., Urbana, IL, 61801, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hergenrother
authors.affiliation: Laboratory of Drosophila Research and School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, P.R. China. hyechan@cuhk.edu.hk.
authors.forename: H Y Edwin
authors.initials: HY
authors.lastname: Chan
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave., Urbana, IL, 61801, USA. sczimmer@illinois.edu.
authors.forename: Steven C
authors.identifier: 0000-0002-5333-3437
authors.initials: SC
authors.lastname: Zimmerman
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D030801:Animals, Genetically Modified; D002232:Carbocyanines / Q000737:chemistry; D057930:Click Chemistry; D061565:Cycloaddition Reaction; D004330:Drosophila; D005456:Fluorescent Dyes / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D009223:Myotonic Dystrophy / Q000188:drug therapy*; D012313:RNA / Q000037:antagonists & inhibitors; D012326:RNA Splicing / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors*; D011972:Receptor, Insulin / Q000235:genetics; D014227:Triazines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D019680:Trinucleotide Repeat Expansion
chemical_list: C569686:Alexa Fluor 647; D000578:Amidines; D002232:Carbocyanines; D005456:Fluorescent Dyes; D008024:Ligands; C493663:MBNL1 protein, human; D016601:RNA-Binding Proteins; D014227:Triazines; D012313:RNA; D011972:Receptor, Insulin
keywords: Click chemistry; Drosophila model; Myotonic dystrophy; RNA recognition; RNA-protein inhibitor