title: Developing bivalent ligands to target CUG triplet repeats, the causative agent of myotonic dystrophy type 1.
abstract: An expanded CUG repeat transcript (CUG(exp)) is the causative agent of myotonic dystrophy type 1 (DM1) by sequestering muscleblind-like 1 protein (MBNL1), a regulator of alternative splicing. On the basis of a ligand (1) that was previously reported to be active in an in vitro assay, we present the synthesis of a small library containing 10 dimeric ligands (4-13) that differ in length, composition, and attachment point of the linking chain. The oligoamino linkers gave a greater gain in affinity for CUG RNA and were more effective when compared to oligoether linkers. The most potent in vitro ligand (9) was shown to be aqueous-soluble and both cell- and nucleus-permeable, displaying almost complete dispersion of MBNL1 ribonuclear foci in a DM1 cell model. Direct evidence for the bioactivity of 9 was observed in its ability to disperse ribonuclear foci in individual live DM1 model cells using time-lapse confocal fluorescence microscopy.
authors.affiliation: Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL, USA.|Department of Chemistry, University of Illinois, Urbana, IL, USA.
authors.forename: Amin Haghighat
authors.initials: AH
authors.lastname: Jahromi
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL, USA.
authors.forename: Kali A
authors.initials: KA
authors.lastname: Miller
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL, USA.
authors.forename: Lien
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL, USA.
authors.forename: Long M
authors.initials: LM
authors.lastname: Luu
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Baranger
authors.affiliation: Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL, USA.|Department of Chemistry, University of Illinois, Urbana, IL, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Zimmerman
mesh_terms: D006801:Humans; D008024:Ligands; D018613:Microscopy, Confocal; D009223:Myotonic Dystrophy / Q000235:genetics*; D011073:Polyamines / Q000138:chemical synthesis* / Q000494:pharmacology; D012313:RNA / Q000235:genetics; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D013816:Thermodynamics; D018911:Trinucleotide Repeats
chemical_list: D008024:Ligands; C493663:MBNL1 protein, human; D011073:Polyamines; D016601:RNA-Binding Proteins; D012313:RNA