Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
Theranostics. 2020 Aug 8;10(22):10141-10153. doi: 10.7150/thno.46985. eCollection 2020.
Despite dramatic advances in drug discovery over the decades, effective therapeutic strategies for cancers treatment are still in urgent demands. PROteolysis TArgeting Chimera (PROTAC), a novel therapeutic modality, has been vigorously promoted in preclinical and clinical applications. Unlike small molecule PROTAC, peptide PROTAC (p-PROTAC) with advantages of high specificity and low toxicity, while avoiding the limitations of shallow binding pockets through large interacting surfaces, provides promising substitutions for E3 ubiquitin ligase complex-mediated ubiquitination of "undruggable proteins". It is worth noting that successful applications of p-PROTAC still have some obstacles, including low stability and poor membrane permeability. Hence, we highlight that p-PROTAC combined with cell-penetrating peptides, constrained conformation technique, and targeted delivery systems could be the future efforts for potential translational research.
尽管几十年来药物发现取得了显著进展，但癌症治疗的有效治疗策略仍迫切需要。PROteolysis TArgeting Chimera（PROTAC）是一种新型的治疗模式，已在临床前和临床应用中得到大力推广。与小分子 PROTAC 不同，肽 PROTAC（p-PROTAC）具有高特异性和低毒性的优点，同时通过大相互作用表面避免了浅结合口袋的限制，为 E3 泛素连接酶复合物介导的“不可成药蛋白”的泛素化提供了有前途的替代品。值得注意的是，p-PROTAC 的成功应用仍然存在一些障碍，包括低稳定性和差的膜通透性。因此，我们强调 p-PROTAC 与穿透肽、约束构象技术和靶向递送系统相结合可能是未来潜在转化研究的努力方向。
