期刊
NUCLEIC ACIDS RESEARCH
卷 39, 期 20, 页码 8881-8890出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkr415
关键词
-
资金
- National Institutes of Health [RO1AR058361, R01AR058361]
- Department of Chemistry
Myotonic dystrophy type 2 (DM2) is an incurable neuromuscular disease caused by expanded CCUG repeats that may exhibit toxicity by sequestering the splicing regulator MBNL1. A series of triaminotriazine- and triaminopyrimidine-based small molecules (ligands 1-3) were designed, synthesized and tested as inhibitors of the MBNL1-CCUG interaction. Despite the structural similarities of the triaminotriazine and triaminopyrimidine units, the triaminopyrimidine-based ligands bind with low micromolar affinity to CCUG repeats (K-d similar to 0.1-3.6 mu M) whereas the triaminotriazine ligands do not bind CCUG repeats. Importantly, these simple and small triaminopyrimidine ligands exhibit both strong inhibition (K-i similar to 2 mu M) of the MBNL1-CCUG interaction and high selectivity for CCUG repeats over other RNA targets. These experiments suggest these compounds are potential lead agents for the treatment of DM2.
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