Recent Advances in PROTAC Technology Toward New Therapeutic Modalities
Recent Advances in PROTAC Technology Toward New Therapeutic Modalities
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DOI：
10.1002/cbdv.202200828
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发表时间：
2022-09
影响因子：
2.9
通讯作者：
Hidetomo Yokoo;Miyako Naganuma;M. Oba;Yosuke Demizu
中科院分区：
文献类型：
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作者：
Hidetomo Yokoo;Miyako Naganuma;M. Oba;Yosuke Demizu
靶向嵌合体（Proteolysis targeting chimeras, PROTACs）是一种通过劫持内源性泛素-蛋白酶体系统来降解疾病相关蛋白的强大技术。使用小分子配体开发了许多双功能PROTACs；一个配体与目标蛋白结合，另一个配体与E3连接酶结合。这些PROTACs的特性各不相同，包括它们与靶蛋白的可逆或不可逆共价结合，它们与正构和变构位点的结合，它们的激动剂或拮抗剂活性，以及它们使用多种配体。此外，寡肽和核苷酸最近被用作替代的靶向配体。PROTACs的特性，如选择性、递送和对耐药的敏感性，可以通过使用各种靶向配体方式来改善。这篇综述介绍了基于小分子的PROTACs的机制和行为，以及使用肽和核酸作为靶向配体的靶向蛋白水解技术。
Proteolysis targeting chimeras (PROTACs) have emerged as a powerful technology for the degradation of disease‐related proteins by the hijacking of the endogenous ubiquitin‐proteasome system. A multitude of bifunctional PROTACs have been developed using small‐molecule ligands; one ligand binds to the target protein of interest and one ligand binds to an E3 ligase. The characteristics of those PROTACs vary, including their reversible or irreversible covalent binding to the target protein, their binding to orthosteric and allosteric sites, their agonist or antagonist activity, and their use of multiple ligands. In addition, oligopeptides and nucleotides have recently been used as alternative targeting ligands. The properties of PROTACs, such as selectivity, delivery and sensitivity to drug resistance, can be improved through the use of a variety of targeting ligand modalities. This minireview introduces the mechanisms and behavior of small‐molecule based PROTACs as well as targeted proteolysis techniques using peptides and nucleic acids as targeting ligands.