Targeting Toxic RNAs that Cause Myotonic Dystrophy Type 1 (DM1) with a Bisamidinium Inhibitor

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• 作者：Chun-Ho Wong ; Lien Nguyen ; Jessie Peh ; Long M. Luu ; Jeannette S. Sanchez ; Stacie L. Richardson ; Tiziano Tuccinardi ; Ho Tsoi ; Wood Yee Chan ; H. Y. Edwin Chan ; Anne M. Baranger ; Paul J. Hergenrother ; Steven C. Zimmerman
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：April 30, 2014
• 年：2014
• 卷：136
• 期：17
• 页码：6355-6361
• 全文大小：435K
• 年卷期：v.136,no.17(April 30, 2014)
• ISSN：1520-5126

文摘

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 DM1 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 卤 2 渭M) and disrupts the MBNL1-r(CUG)₁₂ interaction in vitro (K_i = 8 卤 2 渭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 DM1 Drosophila model was observed after treatment with ligand 3. These results suggest ligand 3 as a lead for the treatment of DM1.