Kim Gibae, Grams R Justin, Hsu Ku-Lung
Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States.
Chem Rev. 2025 Jul 23;125(14):6653-6684. doi: 10.1021/acs.chemrev.5c00001. Epub 2025 May 22.
Targeting intractable proteins remains a key challenge in drug discovery, as these proteins often lack well-defined binding pockets or possess shallow surfaces not readily addressed by traditional drug design. Covalent chemistry has emerged as a powerful solution for accessing protein sites in difficult to ligand regions. By leveraging activity-based protein profiling (ABPP) and LC-MS/MS technologies, academic groups and industry have identified cysteine-reactive ligands that enable selective targeting of challenging protein sites to modulate previously inaccessible biological pathways. Cysteines within a protein are rare, however, and developing covalent ligands that target additional residues hold great promise for further expanding the ligandable proteome. This review highlights recent advancements in targeting amino acids beyond cysteine binding with an emphasis on tyrosine- and lysine-directed covalent ligands and their applications in chemical biology and therapeutic development. We outline the process of developing covalent ligands using chemical proteomic methodology, highlighting recent successful examples and discuss considerations for future expansion to additional amino acid sites on proteins.
靶向难以处理的蛋白质仍然是药物发现中的一个关键挑战，因为这些蛋白质通常缺乏明确的结合口袋，或者具有传统药物设计难以解决的浅表面。共价化学已成为一种强大的解决方案，用于进入难以配体的区域中的蛋白质位点。通过利用基于活性的蛋白质谱分析（ABPP）和液相色谱-串联质谱（LC-MS/MS）技术，学术团体和企业已经鉴定出半胱氨酸反应性配体，这些配体能够选择性地靶向具有挑战性的蛋白质位点，以调节以前无法进入的生物途径。然而，蛋白质中的半胱氨酸很少见，开发靶向其他残基的共价配体对于进一步扩展可配体蛋白质组具有很大的前景。本综述重点介绍了靶向除半胱氨酸结合之外的氨基酸方面的最新进展，重点是酪氨酸和赖氨酸导向的共价配体及其在化学生物学和治疗开发中的应用。我们概述了使用化学蛋白质组学方法开发共价配体的过程，突出了最近的成功实例，并讨论了未来扩展到蛋白质上其他氨基酸位点的考虑因素。
