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通过合性带和PROTAC诱导的降解准USP39的结合体蛋白

Daniel Schäfer^1,2,3, Cristian Prieto-Garcia⁴, Jianhui Wang^1,2

¹Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University Frankfurt am Main, Max-von-Laue-Str. 15, D-60438, Frankfurt am Main, Germany.

Angewandte Chemie (International ed. in English)

|December 22, 2025

概括

研究人员开发了针对USP39的新型PROTACs,这是一个关键的结合体蛋白质,与疾病有关. 这些分子有效降解USP39,为癌症和视网膜色素炎等结合相关疾病提供了新的治疗策略.

科学领域:

分子生物学分子生物学
生物化学生化学
药理学药理学是指药理学的学科.

背景情况:

精确的基因表达调节对细胞功能至关重要;拼接失调与癌症等疾病有关.
乌比基特异性蛋白酶39 (USP39),一种非酶体拼接体因子,是具有挑战性的药物标.

研究的目的:

为了发现小分子接体,准USP39.
开发用于USP39降解的蛋白质分解向嵌合体 (PROTACs).
验证USP39作为拼接相关疾病的治疗标.

主要方法:

发现基于 thiazole 的 USP39 配体.
使用AlphaFold进行结构-活动关系研究.
设计和优化针对USP39的PROTACs (例如,USP39_PROTAC_V1) 使用VHL E3结合酶.
生物物理和生物化学测定三元复合体形成和结合亲和力.
用于USP39降解和全蛋白质组概况的细胞测试.
涉及蛋白质酶体和化抑制的机制研究.

主要成果:

小分子配体通过其指域选择性地参与USP39.
USP39_PROTAC_V1在细胞 (1nM) 中有效地降解USP39,具有最小的目标外影响.
降解依赖于VHL,对蛋白酶体/缩抑制敏感.
USP39的枯竭模仿了已知的5'-splice-site-specific拼接模式. 这是一个很好的方法.

结论:

通过PROTACs向蛋白质降解是有效的USP39.
USP39调制为接相关疾病提供了一个有前途的治疗途径,包括癌症和视网膜色素炎.

关键词:

生物化学和化学生物学是生物化学和化学生物学.药物发现药物发现这就是PROTAC.拼接一些osome.USP39 美国39

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