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目的 基于实时震荡诱导转化（Real-time quaking induced conversion, RT-QuIC）体系评价白藜芦醇苯甲酰肼衍生物对朊蛋白（Prion protein,PrP）聚集的抑制作用，并分析其构效关系。方法 以重组仓鼠PrP90-231为底物、263K感染仓鼠脑匀浆为种子建立RT-QuIC反应体系并验证其稳定性。在优化浓度条件下比较衍生物不同取代基团的抑制效应，采用曲线下面积（Area Under Curve,AUC）归一化指标进行量化分析；选取代表性高、低活性化合物进行分子对接以辅助解释结合机制。结果 RT-QuIC体系重复性良好，适用于化合物筛选；衍生物不同取代基团及位点显著影响抑制效应，其中对位氟取代衍生物抑制最强，而吡啶环取代衍生物整体活性较弱；对接结果显示高活性衍生物具有更高的结合能及多样的相互作用形式。结论 白藜芦醇苯甲酰肼衍生物在RT-QuIC体系中呈现出明确的构效关系，其中对位氟取代为后续结构优化的优势方向。
Abstract：Objective To evaluate the inhibitory effects of benzohydrazide-linked resveratrol derivatives on prion protein(PrP) aggregation using a real-time quaking-induced conversion(RT-QuIC) assay and to analyze their structure–activity relationships(SAR).Methods An RT-QuIC reaction system was established using recombinant hamster PrP(90-231) as the substrate and 263K-infected hamster brain homogenate as the seed, and assay stability was subsequently verified. Under optimized conditions, derivatives bearing different substituents were compared for their inhibitory effects. Aggregation kinetics were quantified using the normalized area under the curve(AUC) values. Representative high-and low-activity compounds were further analyzed by molecular docking to interpret potential binding mechanisms. Results The RT-QuIC system showed good reproducibility and suitablility for compound screening. Both the type and position of substituents markedly influenced inhibitory activity. Para-fluoro-substituted derivatives exhibited the strongest inhibitory activity, whereas pyridyl-substituted derivatives generally showed weaker activity. Docking analysis indicated that highly active derivatives displayed more favorable binding energies and more diverse interaction patterns.Conclusion Benzohydrazide-linked resveratrol derivatives exhibit a clear SAR profile in the RT-QuIC assay, with para-fluoro substitution representing a priority direction for further structural optimization.
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基本信息:
DOI：10.13242/j.cnki.bingduxuebao.260056
中图分类号:R914
引用信息:
[1]李居正,杨微,续芮,等.基于RT‑QuIC的白藜芦醇苯甲酰肼衍生物抗朊蛋白聚集活性评价及构效关系研究[J].病毒学报,2026,42(02):465-474.DOI:10.13242/j.cnki.bingduxuebao.260056.
基金信息:
传染病预防控制国家重点实验室（项目号：2019SKLID401）,题目：宿主天然免疫在朊病毒清除和神经损伤中作用研究~~
2026-03-12
2026-03-12
2026-03-12