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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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Main Authors: 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
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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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title Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation
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