Department of Chemistry, Johns Hopkins University, 3400N. Charles St., Baltimore, MD 21218, USA.
Biomolecular NMR Center, Johns Hopkins University, Baltimore, MD 21218, USA.
Chembiochem. 2021 Aug 17;22(16):2619-2623. doi: 10.1002/cbic.202100247. Epub 2021 Jul 8.
DNA polymerase β (Pol β) is a frequently overexpressed and/or mutated bifunctional repair enzyme. Pol β possesses polymerase and lyase active sites, that are employed in two steps of base excision repair. Pol β is an attractive therapeutic target for which there is a need for inhibitors. Two mechanistically inspired covalent inhibitors (1, IC =21.0 μM; 9, IC =18.7 μM) that modify lysine residues in different Pol β active sites are characterized. Despite modifying lysine residues in different active sites, 1 and 9 inactivate the polymerase and lyase activities of Pol β. Fluorescence anisotropy experiments indicate that they do so by preventing DNA binding. Inhibitors 1 and 9 provide the basis for a general approach to preparing domain selective inhibitors of bifunctional polymerases. Such molecules could prove to be useful tools for studying the role of wild type and mutant forms of Pol β and other polymerases in DNA repair.
DNA 聚合酶 β（Pol β）是一种经常过表达和/或突变的双功能修复酶。Pol β 具有聚合酶和核酸内切酶活性位点，用于碱基切除修复的两个步骤。Pol β 是一个有吸引力的治疗靶点，需要抑制剂。两种基于机制的共价抑制剂（1，IC=21.0 μM；9，IC=18.7 μM），修饰不同 Pol β 活性位点中的赖氨酸残基，对其进行了表征。尽管修饰了不同活性位点中的赖氨酸残基，但 1 和 9 使 Pol β 的聚合酶和核酸内切酶活性失活。荧光各向异性实验表明，它们通过阻止 DNA 结合来实现这一点。抑制剂 1 和 9 为制备双功能聚合酶的结构域选择性抑制剂提供了一般方法的基础。这些分子可能被证明是研究野生型和突变型 Pol β 及其他聚合酶在 DNA 修复中的作用的有用工具。
