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电扫描揭示了对共价结合剂设计的反应热点

Nathalie M Grob¹, Clint Remarcik², Simon L Rössler¹

¹Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States of America.

ACS chemical biology

|December 9, 2023

概括

电扫描识别了的反应部位,以创建蛋白质-蛋白质相互作用 (PPI) 的共价结合物. 这种方法通过使酸能够与具有挑战性的蛋白质标形成稳定的键,迅速开发有针对性的治疗方法.

科学领域:

化学生物学化学生物学
药物发现药物发现药物发现
结构生物学结构生物学

背景情况:

蛋白与蛋白相互作用 (PPI) 在生物过程中至关重要,并且由于它们的大,无特征的结合表面,它们代表了药物开发的具有挑战性的目标.
类是PPI的合适配体,但通常需要增强的结合策略来克服缺乏深层口袋的缺陷.
对PPI目标而言,共价修饰提供了一种改善连接体结合亲和力和持续时间的机制.

研究的目的:

引入和验证一种新的策略,称为"电扫描",用于识别联体上的反应热点.
为了证明电扫描在开发共价结合剂中的应用,用于模型蛋白质-蛋白质相互作用.
评估共价联体在抑制PPI接口上的分子识别方面的潜力.

主要方法:

已知联体的氨酸突变体的生成,以使用氧化添加复合体 (Pd-OAC) 引入蛋白反应性修饰剂.
在生理条件下,通过改性和目标蛋白之间的交叉链接反应来识别反应性热点.
利用一种涉及抗原VL9和主要组织相容性复合体 (MHC) 类I蛋白HLA-E的模型系统.

主要成果:

电扫描成功地在VL9上发现了两个反应热点.
这些热点使有效的蛋白质-联体形成成为可能,在4小时内达到高达87%的转化.
这种交叉链接的被证明抑制了CD94-NKG2A的HLA-E识别,这表明PPI的功能障碍.

结论:

电扫描是一种有效的方法,用于快速发现和开发针对蛋白质-蛋白质相互作用的共价结合剂.
这种方法有助于创建具有增强结合能力的修饰,用于具有挑战性的治疗标.
开发的共价联对调节PPI具有前途,并可能导致新的治疗策略.

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