Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
ACS Chem Biol. 2020 Apr 17;15(4):849-855. doi: 10.1021/acschembio.0c00036. Epub 2020 Mar 18.
RNA repeat expansions cause more than 30 neurological and neuromuscular diseases with no known cures. Since repeat expansions operate via diverse pathomechanisms, one potential therapeutic strategy is to rid them from disease-affected cells, using bifunctional small molecules that cleave the aberrant RNA. Such an approach has been previously implemented for the RNA repeat that causes myotonic dystrophy type 1 [DM1, r(CUG)] with Cugamycin, which is a small molecule that selectively binds r(CUG) conjugated to a bleomycin A5 cleaving module. Herein, we demonstrate that, by replacing bleomycin A5 with deglycobleomycin, an analogue in which the carbohydrate domain of bleomycin A5 is removed, the selectivity of the resulting small-molecule conjugate (DeglycoCugamycin) was enhanced, while maintaining potent and allele-selective cleavage of r(CUG) and rescue of DM1-associated defects. In particular, DeglycoCugamycin did not induce the DNA damage that is observed with high concentrations (25 μM) of Cugamycin, while selectively cleaving the disease-causing allele and improving DM1 defects at 1 μM.
RNA 重复扩展导致超过 30 种神经和神经肌肉疾病，目前尚无已知的治疗方法。由于重复扩展通过不同的病理机制起作用，一种潜在的治疗策略是使用双功能小分子将其从受疾病影响的细胞中清除，这些小分子可以切割异常的 RNA。这种方法以前曾用于导致肌萎缩性侧索硬化症 1 型 [DM1，r(CUG)] 的 RNA 重复，其使用的是 Cugamycin，这是一种小分子，可选择性地结合 r(CUG) 与博来霉素 A5 切割模块连接。在此，我们证明通过用去糖博来霉素代替博来霉素 A5，这种类似物去除了博来霉素 A5 的糖基结构域，所得小分子缀合物（DeglycoCugamycin）的选择性增强，同时保持对 r(CUG) 的有效和等位基因选择性切割，并能挽救 DM1 相关缺陷。特别是，DeglycoCugamycin 不会诱导 Cugamycin 的高浓度（25 μM）观察到的 DNA 损伤，同时选择性地切割致病等位基因并在 1 μM 时改善 DM1 缺陷。
