天然分子胶降解剂的启示

IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Shiyun Cao
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引用次数: 0

摘要

分子胶(MG)降解剂包括植物激素和治疗药物,已成为药物发现领域的热门话题。与二价蛋白水解靶向嵌合体(PROTACs)不同,单价MGs可以通过增强非配体蛋白与E3泛素连接酶的相互作用来触发非配体蛋白的降解。在这里,我分析了天然MG降解剂的特点,将它们与合成的MG降解剂进行了对比,并为优化MGs提供了理论依据。在基于天然 MG 的降解系统中,只有当所有三个伙伴(MG、E3 连接酶和底物)都存在时,才能形成稳定的复合物,而任何两个成分之间的亲和力要么很弱,要么无法检测到。底物降解后,由于 MG 与其受体(E3 连接酶)之间的亲和力很低,因此 MG 会与其受体解离。相反,人工合成的 MG,如免疫调节药物(IMiDs)和 CR8,通过阻断 CRBN 与原生底物的相互作用或占据 CDK12 的活性位点,成为其受体的强效抑制剂。受自然界的启发,IMiDs 与 CRBN 的亲和力可以降低,使这些化合物成为没有 E3 抑制活性的降解剂,从而最大限度地减少对 CRBN 生理底物的干扰。同样,也可以削弱 CR8 与 CDK 的相互作用,使降解剂功能与激酶抑制作用脱钩。为了模仿自然实例并减少副作用,未来应考虑开发缺乏抑制活性的 MG 降解剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Lessons from natural molecular glue degraders.

Molecular glue (MG) degraders include plant hormones and therapeutic drugs and have become a hot topic in drug discovery. Unlike bivalent proteolysis targeting chimeras (PROTACs), monovalent MGs can trigger the degradation of non-ligandable proteins by enhancing their interaction with E3 ubiquitin ligases. Here, I analyze the characteristics of natural MG degraders, contrast them with synthetic ones, and provide a rationale for optimizing MGs. In natural MG-based degradation systems, a stable complex is only formed when all three partners (MG, E3 ligase, and substrate) are present, while the affinities between any two components are either weak or undetectable. After the substrate is degraded, the MG will dissociate from its receptor (E3 ligase) due to their low micromolar affinity. In contrast, synthetic MGs, such as immunomodulatory drugs (IMiDs) and CR8, are potent inhibitors of their receptors by blocking the CRBN-native substrate interaction or by occupying the active site of CDK12. Inspired by nature, the affinities of IMiDs to CRBN can be reduced to make those compounds degraders without the E3-inhibitory activity, therefore, minimizing the interference with the physiological substrates of CRBN. Similarly, the CR8-CDK interaction can be weakened to uncouple the degrader function from the kinase inhibition. To mimic natural examples and reduce side effects, future development of MG degraders that lack the inhibitory activity should be considered.

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来源期刊
Biochemical Society transactions
Biochemical Society transactions 生物-生化与分子生物学
CiteScore
7.80
自引率
0.00%
发文量
351
审稿时长
3-6 weeks
期刊介绍: Biochemical Society Transactions is the reviews journal of the Biochemical Society. Publishing concise reviews written by experts in the field, providing a timely snapshot of the latest developments across all areas of the molecular and cellular biosciences. Elevating our authors’ ideas and expertise, each review includes a perspectives section where authors offer comment on the latest advances, a glimpse of future challenges and highlighting the importance of associated research areas in far broader contexts.
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