Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor.
Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor.
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DOI：
10.1021/ja5012146
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发表时间：
2014-04-30
影响因子：
15
通讯作者：
Zimmerman SC
中科院分区：
文献类型：
--
作者：
Wong CH;Nguyen L;Peh J;Luu LM;Sanchez JS;Richardson SL;Tuccinardi T;Tsoi H;Chan WY;Chan HY;Baranger AM;Hergenrother PJ;Zimmerman SC
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 (Kd = 8 ± 2 μM) and disrupts the MBNL1-r(CUG)12 interaction in vitro (Ki = 8 ± 2 μM). 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.
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能够在体外抑制（CUG）重复RNA-MBNL1相互作用的分子的动态组合选择：发现靶向肌发育症的铅化合物（DM1）。
影响因子：
15
作者：
Gareiss, Peter C.;Sobczak, Krzysztof;McNaughton, Brian R.;Palde, Prakash B.;Thornton, Charles A.;Miller, Benjamin L.
通讯作者：
Miller, Benjamin L.
影响因子：
4
作者：
Coonrod LA;Nakamori M;Wang W;Carrell S;Hilton CL;Bodner MJ;Siboni RB;Docter AG;Haley MM;Thornton CA;Berglund JA
通讯作者：
Berglund JA
影响因子：
64.8
作者：
BUXTON, J;SHELBOURNE, P;JOHNSON, K
通讯作者：
JOHNSON, K
影响因子：
2.9
作者：
Kumar, Arnit;Park, HaJeung;Fang, Pengfei;Parkesh, Raman;Guo, Min;Nettles, Kendall W.;Disney, Matthew D.
通讯作者：
Disney, Matthew D.
影响因子：
14.9
作者：
Krzyzosiak WJ;Sobczak K;Wojciechowska M;Fiszer A;Mykowska A;Kozlowski P
通讯作者：
Kozlowski P