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发现了向蛋白质溶解的嵌合体,该嵌合体的向是使用共价连接体选方法向无法药物处理的蛋白质

Hyeonjun Lee¹, Ju Yeon Lee², Hyunsoo Jang¹

¹College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019, South Korea.

European journal of medicinal chemistry

|November 13, 2023

概括

这项研究引入了一种新方法,用于向蛋白质降解 (TPD),使用向蛋白质溶解的嵌合体 (PROTACs). 这种方法可以降解以前无法处理的蛋白质,从而扩大治疗可能性.

科学领域:

生物化学生化学
化学生物学化学生物学
药物发现药物发现药物发现

背景情况:

使用向蛋白质分解的仿真体 (PROTACs) 的向蛋白质降解 (TPD) 是一个有前途的治疗策略.
参与蛋白质-蛋白质相互作用 (PPI) 的蛋白质与 PROTACs 的降解是具有挑战性的,因为难以识别小分子结合剂.
无法治疗的蛋白质代表了治疗开发中的重大未满足需求.

研究的目的:

为 PROTAC 应用开发一种用于识别与标蛋白结合的化学部分的新方法.
为了使以前无法制药的蛋白质,特别是那些参与PPI的蛋白质,能够有针对性的降解.
通过模型系统验证开发的方法.

主要方法:

使用液体染色学-并联质谱法 (LC-MS/MS) 进行特定地点,基于片段的共价联体选.
二维核磁共振 (2D NMR) 用于评估模拟化合物的可逆结合.
合成包含验证的可逆结合剂的新型PROTACs.
西方斑点分析以确认蛋白质降解.

主要成果:

成功识别了用于向结合的新化学成分.
通过二维NMR证明模拟化合物的可逆结合.
使用人类小鼠双分钟 (MDM) 2作为模型PPI目标的方法的验证.
通过新合成的PROTACs调解的剂量和时间依赖性降解的证实.

结论:

开发的方法方便了使用PROTAC技术来向以前无法药物治疗的蛋白质.
这种方法扩大了向蛋白质降解的范围,以包括具有挑战性的目标,如PPI所涉及的目标.
这些发现为针对由无法药物治疗的目标驱动的疾病的新型治疗策略铺平了道路.

关键词:

选共价性连接体选液体染色学-质谱学 (LC-MS) 是一种鼠标双分钟 (MDM2) 的时间.核磁共振 (NMR) 结合研究研究这就是PROTAC.

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