Spt4/Spt5 is an useful target as it is likely a transcription factor that has implications for long non‐coding RNA repeats related to frontotemporal dementia (FTD) found in the C9orf72 disease pathology. Inhibitors for Spt4/Spt5 using peptides as a starting point for assays as a means for developing small molecules, which could likely lead to therapeutic development for inhibition for Spt4/Spt5 with CNS characteristics. To elucidate the specific steps of identification and modification of key interacting residues from Spt4/Spt5 complex with further effect prediction, a set of different computational methods was applied. Newly characterized, theoretically derived peptides docked on Spt4/Spt5 models, based on X‐ray crystallography sources, allowed us to complete molecular dynamics simulations and docking studies for peptide libraries that give us high confident set of peptides for use to screen for Spt4/Spt5 inhibition. Several peptides with increased specificity to the Spt4/Spt5 interface were found and can be screened in cell‐based assays and enzymatic assays for peptide screens that lead to small molecule campaigns. Spt4/Spt5 comprises an attractive target for neurological diseases, and applying these peptides into a screening campaign will promote the goal of therapeutic searches for FTD drug discovery.

中文翻译：

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Spt4-Spt5 的肽基抑制：针对与 C9orf72 扩增重复相关的转录途径的蛋白质-蛋白质抑制剂。

Spt4/Spt5 是一个有用的靶点，因为它可能是一种转录因子，对 C9orf72 疾病病理学中发现的与额颞叶痴呆 (FTD) 相关的长非编码 RNA 重复具有影响。Spt4/Spt5 抑制剂使用肽作为检测的起点，作为开发小分子的手段，这可能会导致具有 CNS 特征的 Spt4/Spt5 抑制疗法的开发。为了阐明Spt4/Spt5复合物中关键相互作用残基的识别和修饰以及进一步效果预测的具体步骤，应用了一组不同的计算方法。基于 X 射线晶体学源，新表征的理论衍生肽对接在 Spt4/Spt5 模型上，使我们能够完成肽库的分子动力学模拟和对接研究，为我们提供了一组高置信度的肽，用于筛选 Spt4/Spt5抑制。发现了几种对 Spt4/Spt5 界面具有更高特异性的肽，并且可以在基于细胞的测定和酶促测定中进行筛选，以进行肽筛选，从而导致小分子活动。Spt4/Spt5 是神经系统疾病的一个有吸引力的靶标，将这些肽应用于筛选活动将促进 FTD 药物发现的治疗搜索目标的实现。