期刊
NATURE CHEMICAL BIOLOGY
卷 13, 期 2, 页码 188-193出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2251
关键词
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资金
- US National Institutes of Health [DP1NS096898, DP1NS096787]
- Muscular Dystrophy Association [380467]
- Myotonic Dystrophy Foundation
Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, the toxic noncoding repeat expansion (r(CUG)(exp)) that causes myotonic dystrophy type 1 (DM1). We developed several strategies to generate allele-selective small molecules, including non-covalent binding, covalent binding, cleavage and on-site probe synthesis. Covalent binding and cleavage enabled target profiling in cells derived from individuals with DM1, showing precise recognition of r(CUG)(exp). In the on-site probe synthesis approach, small molecules bound adjacent sites in r(CUG)(exp) and reacted to afford picomolar inhibitors via a proximity based click reaction only in DM1-affected cells. We expanded this approach to image r(CUG)(exp) in its natural context.
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