通过Foldamer螺旋模拟和Bis-Thioether拼接进行p53-hDM2相互作用的细胞透性抑制剂
Maxime Neuville1,2, Mathieu Bourgeais1,3, Bo Li1
1Univ. Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, IECB, F-33607 Pessac, France.
Journal of medicinal chemistry
|December 25, 2024
概括
研究人员通过将折叠体与酸结合,开发出受约束的,细胞透的抑制剂. 这些宏环化合物向hDM2,通过参与细胞内的点来显示癌症治疗的潜力.
科学领域:
- 药用化学 医学化学
- 化学生物学 化学生物学
- 结构生物学 结构生物学
背景情况:
- 螺旋式折叠体和α-可以创建具有更好的稳定性的α-螺旋模拟体.
- 之前的工作设计了一种混合-氨酸,针对p53与hDM2.2的相互作用.
- 这项研究增强了折叠剂-杂交的混合物,用于细胞透性抑制剂的交叉链接.
研究的目的:
- 为了设计受约束的,细胞透的体折叠体宏循环,以hDM2.2为目标.
- 评估结构修改对目标参与和细胞活动的影响.
- 调查p53依赖和p53独立的作用机制.
主要方法:
- 基于foldamer-hDM2晶体结构的宏环折叠剂-杂交物的设计和合成.
- 优化化合物的细胞吸收和体外试验.
- 细胞测试以评估细胞毒性活性和p53依赖性.
主要成果:
- 成功生成具有增强约束力的宏环折叠分子-杂交物.
- 鉴定表现出p53-独立细胞毒性的N-终端修饰抑制剂.
- 中性乙化宏环表现出p53依赖的活性.
结论:
- 限制性折分子宏循环是hDM2.2的有效的细胞透性抑制剂.
- 结构性修改决定了细胞活动的机制 (p53依赖或不依赖).
- 这种方法为开发向癌症治疗方法提供了一个有希望的策略.
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