靶向去泛素酶嵌合体(DUBTACs)作为一种潜在的范式转移药物发现方法

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL
Zonghui Ma, Mingxiang Zhou, Haiying Chen, Qiang Shen, Jia Zhou
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引用次数: 0

摘要

通过靶蛋白降解(TPD)开发靶向蛋白水解嵌合体(PROTACs)是一种很有前景的治疗方法。虽然多种疾病是由具有保护功能的关键蛋白的异常泛素化和降解驱动的,但靶蛋白稳定(TPS)而不是TPD正在成为一种独特的治疗方式。deubiquitinase -targeting chimeras (DUBTACs)是一类由deubiquitinase (DUB)和protein-of-interest (POI)靶向配体与连接体结合而成的异双功能蛋白稳定剂,可以使这些蛋白免于异常消除。dubtac以dub依赖的方式稳定poi的水平,从多泛素化和降解的蛋白质中去除泛素。dubtac通过形成POI- dubtac -DUB三元配合物诱导POI与DUB之间产生新的相互作用。本文介绍了TPS方法对人类疾病的治疗益处,并总结了开发dubtac的最新进展。本文还讨论了相关的挑战、机遇和未来展望。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Deubiquitinase-Targeting Chimeras (DUBTACs) as a Potential Paradigm-Shifting Drug Discovery Approach

Deubiquitinase-Targeting Chimeras (DUBTACs) as a Potential Paradigm-Shifting Drug Discovery Approach
Developing proteolysis-targeting chimeras (PROTACs) is well recognized through target protein degradation (TPD) toward promising therapeutics. While a variety of diseases are driven by aberrant ubiquitination and degradation of critical proteins with protective functions, target protein stabilization (TPS) rather than TPD is emerging as a unique therapeutic modality. Deubiquitinase-targeting chimeras (DUBTACs), a class of heterobifunctional protein stabilizers consisting of deubiquitinase (DUB) and protein-of-interest (POI) targeting ligands conjugated with a linker, can rescue such proteins from aberrant elimination. DUBTACs stabilize the levels of POIs in a DUB-dependent manner, removing ubiquitin from polyubiquitylated and degraded proteins. DUBTACs can induce a new interaction between POI and DUB by forming a POI-DUBTAC-DUB ternary complex. Herein, therapeutic benefits of TPS approaches for human diseases are introduced, and recent advances in developing DUBTACs are summarized. Relevant challenges, opportunities, and future perspectives are also discussed.
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来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
期刊介绍: The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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