Targeting Toxic RNAs that Cause Myotonic Dystrophy Type 1 (DM1) with a Bisamidinium Inhibitor
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摘要A working hypothesis for the pathogenesis of myotonic dystrophy type 1 (DM1) involves the aberrant sequestration of an alternative splicing regulator, MBNL1, by expanded CUG repeats, r(CUG)(exp). It has been suggested that a reversal of the myotonia and potentially other symptoms of the DMI disease can be achieved by inhibiting the toxic MBNL1-r(CUG)(exp) interaction. Using rational design, we discovered an RNA-groove binding inhibitor (ligand 3) that contains two triaminotriazine units connected by a bisamidinium linker. Ligand 3 binds r(CUG)(12) with a low micromolar affinity (K-d = 8 +/- 2 mu M) and disrupts the MBNL1-r(CUG)(12) interaction in vitro (K-i = 8 +/- 2 mu M). In addition, ligand 3 is cell and nucleus permeable, exhibits negligible toxicity to mammalian cells, dissolves MBNL1-r(CUG)(exp) ribonuclear foci, and restores misregulated splicing of IR and cTNT in a DM1 cell culture model. Importantly, suppression of r(CUG)(exp) RNA-induced toxicity in a DMI Drosophila model was observed after treatment with ligand 3. These results suggest ligand 3 as a lead for the treatment of DM1.
著者Wong CH, Nguyen L, Peh J, Luu LM, Sanchez JS, Richardson SL, Tuccinardi T, Tsoi H, Chan WY, Chan HYE, Baranger AM, Hergenrother PJ, Zimmerman SC
期刊名稱Journal of the American Chemical Society
出版年份2014
月份4
日期30
卷號136
期次17
出版社AMER CHEMICAL SOC
頁次6355 - 6361
國際標準期刊號0002-7863
語言英式英語
Web of Science 學科類別Chemistry; Chemistry, Multidisciplinary; CHEMISTRY, MULTIDISCIPLINARY

上次更新時間 2021-22-01 於 00:52