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Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation
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 Ogg1-deficient mice are resistant to acute and systemic inflammation, we h...
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creator | Visnes, Torkild Armando, Cazares-Körner Wenjing, Hao Wallner, Olov Masuyer, Geoffrey Loseva, Olga Mortusewicz, Oliver Wiita, Elisee Sarno, Antonio Manoilov, Aleksandr Astorga-Wells, Juan Jemth, Ann-Sofie Pan, Lang Sanjiv, Kumar Karsten, Stella Gokturk, Camilla Grube, Maurice Evert J, Homan Hanna, Bishoy Magdi Fekry Cynthia, Paulin BJ pham, Therese Rasti, Azita Warpman Berglund, Ulrika von Nikolai, Catharina Benitez-Buelga, Carlos Koolmeister, Tobias Ivanic, Dag Iliev, Petar Scobie, Martin Krokan, Hans Einar Baranczewski, Pawel Artursson, Per Altun, Mikael Jenmalm-Jensen, Annika Kalderen, Christina Xueqing, Ba Zubarev, Roman A Stenmark, Pål Boldogh, Istvan Helleday, Thomas |
description | 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 Ogg1-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. |
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Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-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. 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Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-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. 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title | Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation |
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