Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden.
Department of Biotechnology and Nanomedicine, SINTEF Industry, N-7465 Trondheim, Norway.
Science. 2018 Nov 16;362(6416):834-839. doi: 10.1126/science.aar8048.
The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because -deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor-α-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.
炎症的发生与活性氧物种和氧化损伤有关，如 DNA 中的 7,8-二氢-8-氧鸟嘌呤（8-oxoG）。由于 8-氧鸟嘌呤 DNA 糖基化酶 1（OGG1）结合 8-oxoG，并且 - 缺陷小鼠对急性和全身炎症具有抗性，我们假设 OGG1 抑制可能代表预防和治疗炎症的一种策略。我们开发了 TH5487，一种 OGG1 的选择性活性位点抑制剂，它阻碍 OGG1 与 8-oxoG 的结合和修复，并且在小鼠中耐受性良好。TH5487 可防止肿瘤坏死因子-α诱导的促炎基因鸟嘌呤丰富启动子上的 OGG1-DNA 相互作用。这反过来又降低了核因子 κB 和促炎基因表达的 DNA 占有率，导致免疫细胞向小鼠肺部的募集减少。因此，我们提出了一个概念验证，即靶向氧化 DNA 修复可以减轻体内炎症状态。
