针对突变 p53-R175H 的蛋白水解嵌合体前景看好

IF 3.7 3区 化学 Q2 CHEMISTRY, MULTIDISCIPLINARY
Xinzhe Zhuang, Yidan Guo, Xiaozi Sun, Jie Chen, Songbo Xie, Fengtang Yang* and Jingrui Li*, 
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引用次数: 0

摘要

肿瘤抑制蛋白 p53 是各种癌症类型中最常见的突变蛋白之一。值得注意的是,p53 R175H突变是最普遍的热点突变之一。蛋白水解靶向嵌合体(PROTACs)是一类双功能分子,能够利用细胞泛素-蛋白酶体途径促进靶向蛋白降解。尽管 PROTACs 潜力巨大,但针对 p53-R175H 突变蛋白降解的研究却十分有限。在这项研究中,我们利用已知的 p53-R175H 突变和 E3 泛素连接酶 VHL 的多肽配体,开发了一系列基于多肽的 PROTACs。我们的研究结果表明,其中一种基于多肽的 PROTACs 能够在重组表达系统中将 p53-R175H 蛋白引导至蛋白酶体进行降解。此外,通过合成融合了膜穿透肽的融合肽 PROTAC 分子,我们证明了它穿越细胞膜并随后降低 p53-R175H 突变蛋白水平的能力。重要的是,p53-R175H 的降解可减轻细胞的迁移和侵袭。总之,我们的研究引入了一类新型蛋白质降解剂,为治疗与 p53 突变相关的癌症建立了一个基础框架。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Promising Proteolysis-Targeting Chimera for Mutant p53-R175H

The tumor suppressor protein p53 is among the most commonly mutated proteins across a variety of cancer types. Notably, the p53 R175H mutation ranks as one of the most prevalent hotspot mutations. Proteolysis-targeting chimeras (PROTACs) represent a class of bifunctional molecules capable of harnessing the cellular ubiquitin-proteasome pathway to facilitate targeted protein degradation. Despite the potential of PROTACs, limited research has been directed toward the degradation of the p53-R175H mutant protein. In this study, we developed a series of peptide-based PROTACs, leveraging known peptide ligands for both the p53-R175H mutation and the E3 ubiquitin ligase VHL. Our findings indicate that one of these peptide-based PROTACs is capable of directing the p53-R175H protein to the proteasome for degradation within a recombinant expression system. Moreover, by synthesizing a fusion peptide PROTAC molecule that incorporates a membrane-penetrating peptide, we have demonstrated its ability to traverse cellular membranes and subsequently reduce the levels of the p53-R175H mutant protein. Importantly, the degradation of p53-R175H was found to mitigate the cellular migration and invasion. In summary, our study introduces a novel class of protein degraders and establishes a foundational framework for the therapeutic management of cancers associated with p53 mutations.

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来源期刊
ACS Omega
ACS Omega Chemical Engineering-General Chemical Engineering
CiteScore
6.60
自引率
4.90%
发文量
3945
审稿时长
2.4 months
期刊介绍: ACS Omega is an open-access global publication for scientific articles that describe new findings in chemistry and interfacing areas of science, without any perceived evaluation of immediate impact.
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