Gareiss Peter C, Sobczak Krzysztof, McNaughton Brian R, Palde Prakash B, Thornton Charles A, Miller Benjamin L
Department of Biochemistry and Biophysics, University of Rochester, Rochester, New York 14642, USA.
J Am Chem Soc. 2008 Dec 3;130(48):16254-61. doi: 10.1021/ja804398y.
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-(CUG)(109)-GGG RNA with MBNL1 in vitro, with K(i) values in the low micromolar range.
1型强直性肌营养不良症（DM1）是成人中最常见的肌营养不良症形式，是一种RNA介导的疾病。大量扩增的（CUG）重复序列在细胞核中积累，并隔离诸如剪接调节因子MBNL1等RNA结合蛋白。我们采用树脂结合动态组合化学（RBDCC）来鉴定能够抑制MBNL1与（CUG）重复RNA结合的首批化合物实例。对一个理论多样性为11325个成员的RBDCL进行筛选，得到了几个对（CUG）重复RNA具有显著选择性的分子，其对其他序列的结合选择性更高。这些化合物在体外也能够抑制GGG-（CUG）（109）-GGG RNA与MBNL1的相互作用，抑制常数（K i）值在低微摩尔范围内。
