通过基于片段的设计发现YTHDF2联体
Annalisa Invernizzi1, Francesco Nai1, Rajiv Kumar Bedi1
1Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland.
ACS bio & med chem Au
|August 27, 2025
概括
研究人员发现了与YTHDF2结合的新型小分子,YTHDF2是一种识别mRNAN6-腺甲基化的蛋白质. 这些化合物具有调节m6ARNA通路的潜力.
科学领域:
- 生物化学
- 分子生物学
- 药物发现
背景情况:
- N6-腺甲基化 (m6A) 是一种普遍的mRNA修饰.
- YTH域家族蛋白质 (YTHDF1-3) 是m6A的关键细胞质阅读器.
- 针对m6A阅读器提供治疗潜力.
研究的目的:
- 为了确定YTHDF2的小分子抑制剂.
- 确定化合物的结合亲和力和选择性的特征.
- 为了指导m6A结合联体的优化.
主要方法:
- 基于碎片的药物发现方法使用分子对接.
- 对YTHDF2进行大型片段库的体外查.
- 结构引导的优化和同类的合成.
- 生物物理测定包括光极化 (FP) 和均质时间解析光 (HTRF).
- YTHDF2连接体的X射线晶体学
主要成果:
- 查发现了来自50万个分子的六个初始活跃碎片.
- 优化产生了对YTHDF2具有低微分子亲和力的化合物.
- 化合物23对YTHDF2具有很高的亲和力 (Kd=1. 3μM) 和选择性.
- 几种化合物对YTHDF1-3表现出广泛的亲和力,其中一些与YTHDC2结合.
- 六个晶体结构显示了YTHDF2碎片复合体.
结论:
- 成功识别和优化针对YTHDF2的小分子.
- 具有良好的配体效率和低微分子亲和度的配体.
- 与其他YTH读者蛋白相比,具有可选性.
- 提供了对YTHDF2连接体相互作用的结构见解.
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