Zhao Xue Zhi, Barakat Idris A, Lountos George T, Wang Wenjie, Agama Keli, Mahmud Md Rasel Al, Suazo Kiall F, Andresson Thorkell, Pommier Yves, Burke Terrence R
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Commun Chem. 2024 Sep 16;7(1):208. doi: 10.1038/s42004-024-01298-w.
Developing effective inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) has been challenging because of the enzyme shallow catalytic pocket and non-specific substrate binding interactions. Recently, we discovered a quinolone-binding hot spot in TDP1's active site proximal to the evolutionary conserved Y204 and F259 residues that position DNA. Sulfur (VI) fluoride exchange (SuFEx) is a biocompatible click chemistry reaction that enables acylation of protein residues, including tyrosine. Selective protein modifications can provide insights into the biological roles of proteins and inform ligand design. As we report herein, we used SuFEx chemistries to prepare covalent TDP1-bound binders showing site-specific covalent bonds with Y204. Our work presents the first application of SuFEx chemistries to TDP1 ligands. It validates the ability to covalently modify specific TDP1 residues by designed targeting and adds to the chemical biology resource toolbox for studying TDP1.
由于DNA修复酶酪氨酰-DNA磷酸二酯酶1（TDP1）的催化口袋较浅且存在非特异性底物结合相互作用，开发其有效抑制剂一直具有挑战性。最近，我们在TDP1活性位点靠近进化保守的Y204和F259残基（它们定位DNA）的位置发现了一个喹诺酮结合热点。硫（VI）氟交换（SuFEx）是一种生物相容性点击化学反应，能够使包括酪氨酸在内的蛋白质残基发生酰化。选择性蛋白质修饰可以深入了解蛋白质的生物学作用，并为配体设计提供信息。正如我们在此报告的，我们使用SuFEx化学方法制备了与TDP1共价结合的结合剂，这些结合剂与Y204形成了位点特异性共价键。我们的工作展示了SuFEx化学方法在TDP1配体上的首次应用。它验证了通过设计靶向共价修饰特定TDP1残基的能力，并为研究TDP1的化学生物学资源工具箱增添了内容。
