Rationally Designed Small Molecules That Target Both the DNA and RNA Causing Myotonic Dystrophy Type 1
Rationally Designed Small Molecules That Target Both the DNA and RNA Causing Myotonic Dystrophy Type 1
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DOI：
10.1021/jacs.5b09266
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发表时间：
2015-11-11
影响因子：
15
通讯作者：
Zimmerman, Steven C.
中科院分区：
文献类型：
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作者：
Nguyen, Lien;Luu, Long M.;Zimmerman, Steven C.
单药、单靶点治疗方法通常受到复杂疾病病理生物学的限制。我们报告合理设计的，多靶点药物强直性肌营养不良1型（DM1）。DM1起源于DMPK基因中CTG重复序列（CTG（exp））的异常扩增。鉴定为毒性剂的所得扩增的CUG转录物（CUG（exp））隔离重要蛋白质，如肌盲样蛋白（MBNL），经历重复相关的非ATG（RAN）翻译，并可能导致microRNA失调。我们报告了合理设计的小分子，靶向DM1在体外的病理生物学在三个不同的方式，同时作为转录抑制剂，通过抑制异常蛋白质结合的有毒RNA，并作为RNase模拟降解的有毒RNA。在体外，所述试剂显示出（1）结合CTG（exp）并抑制CUG（exp）转录物的形成，（2）结合CUG（exp）并抑制MBNLl的隔离，和（3）以RNA酶样方式切割CUG（exp）。最有效的化合物能够降低DM1模型细胞中的CUG（exp）水平，并且一种化合物逆转DM1果蝇模型中的两种单独的CUG（exp）诱导的表型。
Single-agent, single-target therapeutic approaches are often limited by a complex disease pathobiology. We report rationally designed, multi-target agents for myotonic dystrophy type 1 (DM1). DM1 originates in an abnormal expansion of CTG repeats (CTG(exp)) in the DMPK gene. The resultant expanded CUG transcript (CUG(exp)) identified as a toxic agent sequesters important proteins, such as muscleblind-like proteins (MBNL), undergoes repeat-associated non-ATG (RAN) translation, and potentially causes microRNA dysregulation. We report rationally designed small molecules that target the DM1 pathobiology in vitro in three distinct ways by acting simultaneously as transcription inhibitors, by inhibiting aberrant protein binding to the toxic RNA, and by acting as RNase mimics to degrade the toxic RNA. In vitro, the agents are shown to (1) bind CTG(exp) and inhibit formation of the CUG(exp) transcript, (2) bind CUG(exp) and inhibit sequestration of MBNL1, and (3) cleave CUG(exp) in an RNase-like manner. The most potent compounds are capable of reducing the levels of CUG(exp) in DM1 model cells, and one reverses two separate CUG(exp)-induced phenotypes in a DM1 Drosophila model.