1. Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation
- Author
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Visnes, Torkild, Cazares-Korner, Armando, Hao, Wenjing, 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, Homan, Evert J., Hanna, Bishoy M. F., Paulin, Cynthia B. J., Pham, Therese, Rasti, Azita, Berglund, Ulrika Warpman, von Nicolai, Catharina, Benitez-Buelga, Carlos, Koolmeister, Tobias, Ivanic, Dag, Iliev, Petar, Scobie, Martin, Krokan, Hans E., Baranczewski, Pawel, Artursson, Per, Altun, Mikael, Jensen, Annika Jenmalm, Kalderen, Christina, Ba, Xueqing, Zubarev, Roman A., Stenmark, Pal, Boldogh, Istvan, Helleday, Thomas, Visnes, Torkild, Cazares-Korner, Armando, Hao, Wenjing, 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, Homan, Evert J., Hanna, Bishoy M. F., Paulin, Cynthia B. J., Pham, Therese, Rasti, Azita, Berglund, Ulrika Warpman, von Nicolai, Catharina, Benitez-Buelga, Carlos, Koolmeister, Tobias, Ivanic, Dag, Iliev, Petar, Scobie, Martin, Krokan, Hans E., Baranczewski, Pawel, Artursson, Per, Altun, Mikael, Jensen, Annika Jenmalm, Kalderen, Christina, Ba, Xueqing, Zubarev, Roman A., Stenmark, Pal, Boldogh, Istvan, and Helleday, Thomas
- Abstract
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-alpha-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor kappa B 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.
- Published
- 2018
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