Dynamic combinatorial selection of molecules capable of inhibiting the (CUG) repeat RNA-MBNL1 interaction in vitro: discovery of lead compounds targeting myotonic dystrophy (DM1).
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.
Gareiss
Peter C
PC
Department of Biochemistry and Biophysics, University of Rochester, Rochester, New York 14642, USA.
Sobczak
Krzysztof
K
McNaughton
Brian R
BR
Palde
Prakash B
PB
Thornton
Charles A
CA
Miller
Benjamin L
BL
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
D008024:Ligands; D016601:RNA-Binding Proteins; D007854:Lead; D012313:RNA