Familial dysautonomia is a debilitating congenital neurodegenerative disorder with no causative therapy. It is caused by a homozygous mutation in ELP1 gene, resulting in the production of the transcript lacking exon 20. The compounds studied as potential treatments include the clinical candidate kinetin, a plant hormone from the cytokinin family. We explored the relationship between the structure of a set of kinetin derivatives (N = 72) and their ability to correct aberrant splicing of the ELP1 gene. Active compounds can be obtained by the substitution of the purine ring with chlorine and fluorine at the C2 atom, with a small alkyl group at the N7 atom, or with diverse groups at the C8 atom. On the other hand, a substitution at the N3 or N9 atoms resulted in a loss of activity. We successfully tested a hypothesis inspired by the remarkable tolerance of the position C8 to substitution, postulating that the imidazole of the purine moiety is not required for the activity. We also evaluated the activity of phytohormones from other families, but none of them corrected ELP1 mRNA aberrant splicing. A panel of in vitro ADME assays, including evaluation of transport across model barriers, stability in plasma and in the presence of liver microsomal fraction as well as plasma protein binding, was used for an initial estimation of the potential bioavailability of the active compounds. Finally, a RNA-seq data suggest that 8-aminokinetin modulates expression spliceosome components.

中文翻译：

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激动素衍生物校正 ELP1 前体 mRNA 的异常剪接 – 结构活性关系研究


家族性自主神经功能障碍是一种使人衰弱的先天性神经退行性疾病，没有致病治疗。它是由 ELP1 基因的纯合突变引起的，导致产生缺乏外显子 20 的转录本。作为潜在治疗方法研究的化合物包括临床候选激动素，一种来自细胞分裂素家族的植物激素。我们探讨了一组激肽衍生物的结构 （N = 72） 与它们纠正 ELP1 基因异常剪接的能力之间的关系。活性化合物可以通过在 C2 原子处用氯和氟取代嘌呤环，在 N7 原子处用小烷基取代，或在 C8 原子处用不同的基团取代来获得。另一方面，N3 或 N9 原子的取代导致活性丧失。我们成功地检验了一个假设，该假设受到位置 C8 对取代的显着耐受性的启发，假设该活性不需要嘌呤部分的咪唑。我们还评估了来自其他家族的植物激素的活性，但没有一个家族纠正了 ELP1 mRNA 异常剪接。一组体外 ADME 测定，包括跨模型屏障的运输、血浆中稳定性和肝微粒体分数存在下的稳定性以及血浆蛋白结合，用于初步估计活性化合物的潜在生物利用度。最后，RNA-seq 数据表明 8-氨基激肽调节剪接体组分的表达。