PROTACs to address the challenges facing small molecule inhibitors.
PROTACs to address the challenges facing small molecule inhibitors.
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DOI：
10.1016/j.ejmech.2020.112993
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发表时间：
2021-01-15
影响因子：
6.7
通讯作者：
Xiao X
中科院分区：
文献类型：
--
作者：
Martín-Acosta P;Xiao X
小分子蛋白质抑制剂是研究靶蛋白生物学的重要药物和关键化学工具。各种组学技术的进步推动了发现疾病相关蛋白的步伐。将这些发现转化为人类的利益需要我们开发特定的化学物质来抑制蛋白质。然而，传统的小分子抑制剂与正构或变构位点的结合面临重大挑战。这些挑战包括药物选择性、治疗抗性以及药物化的非药物化蛋白和多结构域蛋白。为了解决这些挑战，已经提出了PROteolysis Targeting Chimera（PROTAC）。PROTAC是异双功能分子，其含有通过化学接头连接的目的蛋白的结合配体和E3连接酶募集配体。PROTAC与其靶蛋白的结合将使E3连接酶紧密接近，以引发靶蛋白的多聚泛素化，从而导致其蛋白酶体介导的降解。与小分子抑制剂不同，PROTAC以催化方式完全实现靶蛋白降解。在这篇综述中，我们分析了PROTAC设计的最新进展，讨论了PROTAC如何解决小分子抑制剂所面临的挑战，以提供具有高选择性和有效性的下一代药物和化学工具。我们还提供了我们对未来的承诺和PROTAC面临的潜在限制的观点。克服PROTAC这些局限性的研究将进一步增强PROTAC对人类利益的承诺。
Small molecule inhibitors of proteins represent important medicines and critical chemical tools to investigate the biology of the target proteins. Advances in various -omics technologies have fueled the pace of discovery of disease-relevant proteins. Translating these discoveries into human benefits requires us to develop specific chemicals to inhibit the proteins. However, traditional small molecule inhibitors binding to orthosteric or allosteric sites face significant challenges. These challenges include drug selectivity, therapy resistance as well as drugging undruggable proteins and multi-domain proteins. To address these challenges, PROteolysis TArgeting Chimera (PROTAC) has been proposed. PROTACs are heterobifunctional molecules containing a binding ligand for a protein of interest and E3 ligase-recruiting ligand that are connected through a chemical linker. Binding of a PROTAC to its target protein will bring a E3 ligase in close proximity to initiate polyubiquitination of the target protein ensuing its proteasome-mediated degradation. Unlike small molecule inhibitors, PROTACs achieve target protein degradation in its entirety in a catalytical fashion. In this review, we analyze recent advances in PROTAC design to discuss how PROTACs can address the challenges facing small molecule inhibitors to potentially deliver next-generation medicines and chemical tools with high selectivity and efficacy. We also offer our perspectives on the future promise and potential limitations facing PROTACs. Investigations to overcome these limitations of PROTACs will further enhance the promise of PROTACs for human benefits.
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