Howard Hughes Medical Institute, New Haven, CT, USA.
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
Nat Chem Biol. 2018 Dec;14(12):1073-1078. doi: 10.1038/s41589-018-0142-0. Epub 2018 Oct 15.
Specific RNA structures control numerous metabolic processes that impact human health, and yet efforts to target RNA structures de novo have been limited. In eukaryotes, the self-splicing group II intron is a mitochondrial RNA tertiary structure that is absent in vertebrates but essential for respiration in plants, fungi and yeast. Here we show that this RNA can be targeted through a process of high-throughput in vitro screening, SAR and lead optimization, resulting in high-affinity compounds that specifically inhibit group IIB intron splicing in vitro and in vivo and lack toxicity in human cells. The compounds are potent growth inhibitors of the pathogen Candida parapsilosis, displaying antifungal activity comparable to that of amphotericin B. These studies demonstrate that RNA tertiary structures can be successfully targeted de novo, resulting in pharmacologically valuable compounds.
特定的 RNA 结构控制着许多影响人类健康的代谢过程，但从头设计针对 RNA 结构的方法一直受到限制。在真核生物中，自我剪接的 II 组内含子是一种线粒体 RNA 三级结构，在脊椎动物中不存在，但对植物、真菌和酵母的呼吸至关重要。在这里，我们展示了可以通过高通量体外筛选、SAR 和先导化合物优化的过程来靶向这种 RNA，从而得到高亲和力的化合物，这些化合物可以特异性地抑制 IIB 组内含子的体外和体内剪接，并且在人细胞中没有毒性。这些化合物是病原体近平滑假丝酵母的有效生长抑制剂，显示出与两性霉素 B 相当的抗真菌活性。这些研究表明，可以成功地从头设计靶向 RNA 三级结构，从而产生具有药理价值的化合物。
