Departments of Chemistry and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
Department of Chemistry, Florida Atlantic University, John D. MacArthur Campus, Jupiter, FL 33458, USA.
Chembiochem. 2020 Nov 16;21(22):3229-3233. doi: 10.1002/cbic.202000445. Epub 2020 Aug 26.
RNA molecules both contribute to and are causative of many human diseases. One method to perturb RNA function is to target its structure with small molecules. However, discovering bioactive ligands for RNA targets is challenging. Here, we show that the bioactivity of a linear dimeric ligand that inactivates the RNA trinucleotide repeat expansion that causes myotonic dystrophy type 1 [DM1; r(CUG) ] can be improved by macrocyclization. Indeed, the macrocyclic compound is ten times more potent than the linear compound for improving DM1-associated defects in cells, including in patient-derived myotubes (muscle cells). This enhancement in potency is due to the macrocycle's increased affinity and selectively for the target, which inhibit r(CUG) 's toxic interaction with muscleblind-like 1 (MBNL1), and its superior cell permeability. Macrocyclization could prove to be an effective way to enhance the bioactivity of modularly assembled ligands targeting RNA.
RNA 分子既可以促成也可以导致许多人类疾病。一种干扰 RNA 功能的方法是用小分子靶向其结构。然而，发现 RNA 靶标的生物活性配体具有挑战性。在这里，我们表明，一种线性二聚体配体的生物活性可以通过大环化来提高，该配体使导致肌萎缩性侧索硬化症 1 型 [DM1；r(CUG)] 的 RNA 三核苷酸重复扩展失活。事实上，与线性化合物相比，该大环化合物在改善细胞中与 DM1 相关的缺陷方面的效力要强十倍，包括在患者来源的肌管（肌肉细胞）中。这种效力的增强是由于大环化合物对靶标的亲和力和选择性增加，从而抑制 r(CUG) 与肌肉萎缩蛋白样 1 (MBNL1) 的毒性相互作用，以及其优越的细胞通透性。大环化可能被证明是一种有效提高针对 RNA 的模块化组装配体生物活性的方法。
