Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
J Med Chem. 2020 Jul 23;63(14):7827-7839. doi: 10.1021/acs.jmedchem.0c00558. Epub 2020 Jul 13.
RNA repeat expansions are responsible for more than 30 incurable diseases. Among them is myotonic dystrophy type 1 (DM1), the most common form of adult on-set muscular dystrophy. DM1 is caused by an r(CUG) repeat expansion [r(CUG)] located in the 3' untranslated region (UTR) of the dystrophia myotonica protein kinase gene. This repeat expansion is highly structured, forming a periodic array of 5'CG/3'GC internal loop motifs. We therefore designed dimeric compounds that simultaneously bind two of these motifs by connecting two RNA-binding modules with peptoid linkers of different geometries and lengths. The optimal linker contains two proline residues and enhances compound affinity. Equipping this molecule with a bleomycin A5 cleaving module converts the simple binding compound into a potent allele-selective cleaver of r(CUG). This study shows that the linker in modularly assembled ligands targeting RNA can be optimized to afford potent biological activity.
RNA 重复扩展是导致 30 多种无法治愈疾病的原因之一。其中包括肌强直性营养不良 1 型（DM1），这是最常见的成年发病型肌肉营养不良症。DM1 是由位于肌强直性营养不良蛋白激酶基因 3'非翻译区（UTR）的 r(CUG)重复扩展[r(CUG)]引起的。这种重复扩展具有高度的结构，形成了一个周期性的 5'CG/3'GC 内部环基序阵列。因此，我们设计了二聚体化合物，通过用不同几何形状和长度的肽连接子连接两个 RNA 结合模块，同时结合两个这样的基序。最佳连接子包含两个脯氨酸残基，并增强了化合物的亲和力。用博来霉素 A5 切割模块装备这个分子，将简单的结合化合物转化为 r(CUG)的有效等位基因选择性切割剂。这项研究表明，针对 RNA 的模块化组装配体中的连接子可以进行优化，以提供有效的生物学活性。
