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Specificity, synergy, and mechanisms of splice-modifying drugs
Nature Communications ( IF 14.7 ) Pub Date : 2024-02-29 , DOI: 10.1038/s41467-024-46090-5
Yuma Ishigami 1 , Mandy S Wong 1, 2 , Carlos Martí-Gómez 1 , Andalus Ayaz 1 , Mahdi Kooshkbaghi 1, 3 , Sonya M Hanson 4 , David M McCandlish 1 , Adrian R Krainer 1 , Justin B Kinney 1
Affiliation  

Drugs that target pre-mRNA splicing hold great therapeutic potential, but the quantitative understanding of how these drugs work is limited. Here we introduce mechanistically interpretable quantitative models for the sequence-specific and concentration-dependent behavior of splice-modifying drugs. Using massively parallel splicing assays, RNA-seq experiments, and precision dose-response curves, we obtain quantitative models for two small-molecule drugs, risdiplam and branaplam, developed for treating spinal muscular atrophy. The results quantitatively characterize the specificities of risdiplam and branaplam for 5’ splice site sequences, suggest that branaplam recognizes 5’ splice sites via two distinct interaction modes, and contradict the prevailing two-site hypothesis for risdiplam activity at SMN2 exon 7. The results also show that anomalous single-drug cooperativity, as well as multi-drug synergy, are widespread among small-molecule drugs and antisense-oligonucleotide drugs that promote exon inclusion. Our quantitative models thus clarify the mechanisms of existing treatments and provide a basis for the rational development of new therapies.



中文翻译:


剪接修饰药物的特异性、协同作用和机制



靶向前 mRNA 剪接的药物具有巨大的治疗潜力,但对这些药物如何发挥作用的定量理解有限。在这里,我们介绍了剪接修饰药物的序列特异性和浓度依赖性行为的可机械解释的定量模型。使用大规模并行剪接测定、RNA-seq 实验和精确的剂量反应曲线,我们获得了两种小分子药物 risdiplam 和 branaplam 的定量模型,这两种药物是为治疗脊髓性肌萎缩症而开发的。结果定量表征了 risdiplam 和 branaplam 对 5' 剪接位点序列的特异性,表明 branaplam 通过两种不同的相互作用模式识别 5' 剪接位点,并与SMN2外显子 7 处 risdiplam 活性的流行双位点假设相矛盾。研究表明,异常的单药协同作用以及多药协同作用在促进外显子包含的小分子药物和反义寡核苷酸药物中普遍存在。因此,我们的定量模型阐明了现有治疗的机制,并为新疗法的合理开发提供了基础。

更新日期:2024-03-02
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