Dynamic Combinatorial Selection of Molecules Capable of Inhibiting the (CUG) Repeat RNA-MBNL1 Interaction In Vitro: Discovery of Lead Compounds Targeting Myotonic Dystrophy (DM1)

被引：148

作者：

Gareiss, Peter C. ^{[2
,5
]}

Sobczak, Krzysztof ^{[4
]}

McNaughton, Brian R. ^{[3
,5
]}

Palde, Prakash B. ^{[2
,5
]}

Thornton, Charles A. ^{[4
]}

Miller, Benjamin L. ^{[1
,2
,5
]}

机构：

[1] Univ Rochester, Dept Dermatol, Rochester, NY 14642 USA

[2] Univ Rochester, Dept Biochem & Biophys, Rochester, NY 14642 USA

[3] Univ Rochester, Dept Chem, Rochester, NY 14642 USA

[4] Univ Rochester, Dept Neurol, Rochester, NY 14642 USA

[5] Univ Rochester, Ctr Future Hlth, Rochester, NY 14642 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2008年 / 130卷 / 48期

关键词：

D O I：

10.1021/ja804398y

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults, is an RNA-mediated disease. Dramatically expanded (CUG) repeats accumulate in nuclei and sequester RNA-binding proteins such as the splicing regulator MBNL1. We have employed resin-bound dynamic combinatorial chemistry (RBDCC) to identify the first examples of compounds able to inhibit MBNL1 binding to (CUG) repeat RNA, Screening an RBDCL with a theoretical diversity of 11 325 members yielded several molecules with significant selectivity for binding to (CUG) repeat RNA over other sequences. These compounds were also able to inhibit the interaction of GGG-(CLlG)(109)-GGG RNA with MBNL1 in vitro, with K-i values in the low micromolar range.

引用

页码：16254 / 16261

页数：8

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