Wang Huidan, Chen Miao, Zhang Xiaoyuan, Xie Songbo, Qin Jie, Li Jingrui
School of Life Sciences and Medicine, Shandong University of Technology, Zibo, 255000, China.
Curr Med Chem. 2024;31(2):208-222. doi: 10.2174/0929867330666230130121822.
Proteolysis-targeting chimeras (PROTACs) are an attractive means to target previously undruggable or drug-resistant mutant proteins. While small molecule-based PROTACs are stable and can cross cell membranes, there is limited availability of suitable small molecule warheads capable of recruiting proteins to an E3 ubiquitin ligase for degradation. With advances in structural biology and in silico protein structure prediction, it is now becoming easier to define highly selective peptides suitable for PROTAC design. As a result, peptide-based PROTACs are becoming a feasible proposition for targeting previously "undruggable" proteins not amenable to small molecule inhibition. In this review, we summarize recent progress in the design and application of peptide-based PROTACs as well as several practical approaches for obtaining candidate peptides for PROTACs. We also discuss the major hurdles preventing the translation of peptide-based PROTACs from bench to bedside, such as their delivery and bioavailability, with the aim of stimulating discussion about how best to accelerate the clinical development of peptide- based PROTACs in the near future.
蛋白酶靶向嵌合体（PROTACs）是一种靶向此前难以成药或耐药突变蛋白的颇具吸引力的手段。虽然基于小分子的PROTACs稳定且能穿过细胞膜，但能够将蛋白招募至E3泛素连接酶进行降解的合适小分子弹头的可用性有限。随着结构生物学和计算机辅助蛋白质结构预测的进展，现在定义适合PROTAC设计的高选择性肽变得更加容易。因此，基于肽的PROTACs正成为靶向此前不适合小分子抑制的“难以成药”蛋白的可行方案。在本综述中，我们总结了基于肽的PROTACs设计与应用的最新进展以及获取PROTACs候选肽的几种实用方法。我们还讨论了阻碍基于肽的PROTACs从实验室走向临床应用的主要障碍，如它们的递送和生物利用度，目的是激发关于如何在不久的将来最好地加速基于肽的PROTACs临床开发的讨论。
