F. Hoffmann-La Roche Ltd., Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel, 4070, Switzerland.
Cold Spring Harbor Laboratory, P.O. Box 100, 1 Bungtown Road, Cold Spring Harbor, New York, NY, 11724, USA.
Nat Commun. 2017 Nov 14;8(1):1476. doi: 10.1038/s41467-017-01559-4.
Small molecule splicing modifiers have been previously described that target the general splicing machinery and thus have low specificity for individual genes. Several potent molecules correcting the splicing deficit of the SMN2 (survival of motor neuron 2) gene have been identified and these molecules are moving towards a potential therapy for spinal muscular atrophy (SMA). Here by using a combination of RNA splicing, transcription, and protein chemistry techniques, we show that these molecules directly bind to two distinct sites of the SMN2 pre-mRNA, thereby stabilizing a yet unidentified ribonucleoprotein (RNP) complex that is critical to the specificity of these small molecules for SMN2 over other genes. In addition to the therapeutic potential of these molecules for treatment of SMA, our work has wide-ranging implications in understanding how small molecules can interact with specific quaternary RNA structures.
小分子剪接修饰物以前被描述为靶向一般剪接机制，因此对个别基因的特异性低。已经鉴定出几种能够纠正 SMN2（运动神经元 2 存活）基因剪接缺陷的有效分子，这些分子正在成为脊髓性肌萎缩症（SMA）的潜在治疗方法。在这里，我们通过结合 RNA 剪接、转录和蛋白质化学技术，表明这些分子直接结合到 SMN2 前体 mRNA 的两个不同部位，从而稳定一个尚未确定的核糖核蛋白（RNP）复合物，这对于这些小分子对 SMN2 的特异性至关重要，而对其他基因则没有特异性。除了这些分子在治疗 SMA 方面的治疗潜力外，我们的工作对于理解小分子如何与特定的四级 RNA 结构相互作用具有广泛的意义。
