化学
药物发现
计算生物学
免疫系统
免疫疗法
蛋白质降解
配体(生物化学)
泛素
药理学
生物
生物化学
免疫学
医学
受体
基因
作者
Chao Wang,Yujing Zhang,Junwen Deng,Bing Liang,Dongming Xing
标识
DOI:10.1016/j.ejmech.2023.115127
摘要
Traditional chemotherapy and immunotherapy are primary disease-treatment strategies. However, they face numerous challenges, including limited therapeutic benefits, off-target effects, serious adverse effects, drug resistance, long half-life time, poor oral bioavailability, and drugging undruggable proteins. Proteolytic targeted chimeras (PROTACs) were suggested to solve these problems. PROTACs are heterogeneous functional molecules linked by a chemical linker and contain a binding ligand for the protein of interest and a recruiting ligand for the E3 ligand. The binding of a PROTAC to a target protein brings the E3 ligand enzyme into proximity, initiating polyubiquitination of the target protein, followed by protease-mediated degradation. To date, PROTACs against dozens of immunological targets have been successfully developed, many of which have been clinically validated drug targets, and several have entered clinical trials for immune-related diseases. This article reviews the role of PROTACs-mediated degradation of critical proteins in immune disorders and cancer immunotherapy. Chemical structures, cellular and in vivo activities, and pharmacodynamics of these PROTACs are summarized. Lastly, we also discuss the prospects and potential limitations that PROTACs face.
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