title: Dynamic combinatorial selection of molecules capable of inhibiting the (CUG) repeat RNA-MBNL1 interaction in vitro: discovery of lead compounds targeting myotonic dystrophy (DM1).
abstract: Myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults, is an RNA-mediated disease. Dramatically expanded (CUG) repeats accumulate in nuclei and sequester RNA-binding proteins such as the splicing regulator MBNL1. We have employed resin-bound dynamic combinatorial chemistry (RBDCC) to identify the first examples of compounds able to inhibit MBNL1 binding to (CUG) repeat RNA. Screening an RBDCL with a theoretical diversity of 11 325 members yielded several molecules with significant selectivity for binding to (CUG) repeat RNA over other sequences. These compounds were also able to inhibit the interaction of GGG-(CUG)(109)-GGG RNA with MBNL1 in vitro, with K(i) values in the low micromolar range.
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester, Rochester, New York 14642, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Gareiss
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Sobczak
authors.forename: Brian R
authors.initials: BR
authors.lastname: McNaughton
authors.forename: Prakash B
authors.initials: PB
authors.lastname: Palde
authors.forename: Charles A
authors.initials: CA
authors.lastname: Thornton
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Miller
mesh_terms: D020650:Combinatorial Chemistry Techniques; D019281:Dimerization; D007854:Lead / Q000737:chemistry*; D008024:Ligands; D009223:Myotonic Dystrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012313:RNA / Q000737:chemistry* / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020080:Tandem Repeat Sequences
chemical_list: D008024:Ligands; D016601:RNA-Binding Proteins; D007854:Lead; D012313:RNA