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希佩尔 - 林道埃隆金C&B综合体的NMR基片屏幕

Kangsa Amporndanai¹, Jade M Katinas¹, Ashima Chopra¹

¹Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States.

ACS medicinal chemistry letters

|August 20, 2025

概括

研究人员发现了用于VHL招募PROTAC的新型非素VHL配体. 这一突破解决了开发口服生物利用药物的挑战,超越了传统的基于的VHL结合剂.

科学领域:

生物化学
药物发现
结构生物学

背景情况:

希佩尔-林道 (VHL) E3链酶对于培养蛋白解向基因组 (PROTACs) 是至关重要的.
目前的VHL招募PROTAC通常使用基于氧的配体,模仿内源基质.
这些基于的配体在PROTAC开发中对口服生物可用性构成重大挑战.

研究的目的:

为了识别新的非性VHL配体.
克服VHL招募PROTAC中的基配体的局限性.
探索替代VHL连接物支架以改善口服生物利用性.

主要方法:

使用基于NMR的碎片选方法.
针对VHL-Elongin C-Elongin B (VCB) 综合体.
使用X射线结晶学验证的结合相互作用.

主要成果:

在VCB复合体内确定了几个与HIF1α活性部位结合的碎片.
这些结果代表了非基VHL配体.
证明了发现替代VHL绑定动机的可行性.

结论:

发现非素VHL配体为PROTAC设计开辟了新的途径.
这一发现有助于开发口服可生物利用的VHL招募PROTAC.
为下一代基于VHL的向蛋白质降解疗法提供基础.

关键词:

E3 连接酶核磁共振扫描仪这里是 PROTAC 在VHL 基于片段的屏幕

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