The role of flexibility in the rational design of modularly assembled ligands targeting the RNAs that cause the myotonic dystrophies.

ABSTRACT: Modularly assembled ligands were designed to target the RNAs that cause two currently untreatable neuromuscular disorders, myotonic dystrophy types 1 (DM1) and 2 (DM2). DM1 is caused by an expanded repeating sequence of CUG, and DM2 is caused by expanded CCUG repeats. Both are present in noncoding regions and fold into hairpins with either repeating 1x1 nucleotide UU (DM1) or 2x2 nucleotide 5'-CU/3'-UC (DM2) internal loops separated by two GC pairs. The repeats are toxic because they sequester the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Rational design of ligands targeting these RNAs was enabled by a database of RNA motif-ligand partners compiled by using two-dimensional combinatorial screening (2DCS). One 2DCS study found that the 6''-azido-kanamycin A module binds inte

SUBMITTER: Disney MD 

PROVIDER: S-EPMC2848078 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature