Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China.
Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Bioessays. 2018 Apr;40(4):e1700247. doi: 10.1002/bies.201700247. Epub 2018 Feb 23.
Proteolysis-targeting chimeric molecules (PROTACs) represent an emerging technique that is receiving much attention for therapeutic intervention. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The hetero-bifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate "undruggable" protein targets, such as transcription factors and non-enzymatic proteins, which are not limited to physiological substrates of the ubiquitin-proteasome system. These findings indicate great prospects for PROTACs in the development of therapeutics. However, there are several limitations related to poor stability, biodistribution, and penetrability in vivo. This review provides an overview of the main PROTAC-based approaches that have been developed and discusses the promising opportunities and considerations for the application of this technology in therapies and drug discovery.
蛋白水解靶向嵌合体（PROTACs）是一种新兴技术，因其在治疗干预方面的潜力而备受关注。其作用机制是通过劫持泛素 E3 连接酶来促进蛋白降解，从而抑制蛋白功能。杂合双功能 PROTACs 包含一个募集 E3 连接酶的配体、一个连接子和另一个与目标蛋白结合的配体。因此，PROTACs 具有极大的潜力来消除“不可成药”的蛋白靶点，如转录因子和非酶蛋白，而且其并不局限于泛素-蛋白酶体系统的生理底物。这些发现表明 PROTACs 在治疗药物开发方面具有广阔的前景。然而，PROTACs 也存在一些局限性，如稳定性差、体内生物分布和通透性差等。本综述概述了已开发的主要基于 PROTAC 的方法，并讨论了该技术在治疗和药物发现中的应用的有前景的机会和考虑因素。
