Abstract：
: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.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Rzuczek SG,Colgan LA,Nakai Y,Cameron MD,Furling D,Yasuda R,Disney MDdoi
10.1038/nchembio.2251subject
Has Abstractpub_date
2017-02-01 00:00:00pages
188-193issue
2eissn
1552-4450issn
1552-4469pii
nchembio.2251journal_volume
13pub_type
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