Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China.
Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China.
Eur J Med Chem. 2021 Apr 15;216:113247. doi: 10.1016/j.ejmech.2021.113247. Epub 2021 Jan 31.
As a newly emerged technology, PROTAC (proteolysis targeting chimera) is a promising therapeutic strategy for varieties of diseases. Unlike small molecule inhibitors, PROTACs catalytically induce target proteins degradation, including currently "undruggable" target proteins. In addition, PROTACs can be a potentially successful strategy to overcome drug resistance. IAPs can inhibit apoptosis by inhibiting caspase, and also exhibits the activity of E3 ubiquitin ligase. Specific and nongenetic IAP-based protein erasers (SNIPERs) are hybrid molecules that designed based on IAPs, and used to degrade the target proteins closely associated with diseases. Their structures consist of three parts, including target protein ligand, E3 ligase ligand and the linker between them. SNIPERs (PROTACs) degrade diseases-associated proteins through human inherent ubiquitin-proteasome system. So far, many SNIPERs have been developed to treat diseases that difficult to handle by traditional methods, such as radiotherapy, chemotherapy and small molecule inhibitors, and showed promising prospects in application. In this paper, the recent advances of SNIPERs were summarized, and the chances and challenges associated with this area were also highlighted.
作为一种新兴的技术，PROTAC（蛋白水解靶向嵌合体）是治疗多种疾病的有前途的治疗策略。与小分子抑制剂不同，PROTACs 催化诱导靶蛋白降解，包括目前“不可成药”的靶蛋白。此外，PROTACs 可能是克服耐药性的潜在有效策略。IAPs 通过抑制半胱天冬酶来抑制细胞凋亡，并且还表现出 E3 泛素连接酶的活性。基于 IAP 的特异性和非遗传蛋白橡皮擦（SNIPERs）是基于 IAPs 设计的杂合分子，用于降解与疾病密切相关的靶蛋白。它们的结构由三部分组成，包括靶蛋白配体、E3 连接酶配体和它们之间的连接子。SNIPERs（PROTACs）通过人体固有泛素-蛋白酶体系统降解与疾病相关的蛋白质。到目前为止，已经开发了许多 SNIPERs 来治疗传统方法难以处理的疾病，如放疗、化疗和小分子抑制剂，并在应用中显示出广阔的前景。本文总结了 SNIPERs 的最新进展，并强调了该领域的机遇和挑战。
