Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation

Torkild Visnes, Armando Cázares-Körner, Wenjing Hao, Olov Wallner, Geoffrey Masuyer, Olga Loseva, Oliver Mortusewicz, Elisée Wiita, Antonio Sarno, Aleksandr Manoilov, Juan Astorga-Wells, Ann Sofie Jemth, Lang Pan, Kumar Sanjiv, Stella Karsten, Camilla Gokturk, Maurice Grube, Evert J. Homan, Bishoy M.F. Hanna, Cynthia B.J. PaulinTherese Pham, Azita Rasti, Ulrika Warpman Berglund, Catharina Von Nicolai, Carlos Benitez-Buelga, Tobias Koolmeister, Dag Ivanic, Petar Iliev, Martin Scobie, Hans E. Krokan, Pawel Baranczewski, Per Artursson, Mikael Altun, Annika Jenmalm Jensen, Christina Kalderén, Xueqing Ba, Roman A. Zubarev, Pål Stenmark, Istvan Boldogh, Thomas Helleday

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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–a–induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor kB 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.

Original languageEnglish (US)
Pages (from-to)834-839
Number of pages6
JournalScience
Volume362
Issue number6416
DOIs
StatePublished - Nov 16 2018

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Visnes, T., Cázares-Körner, A., Hao, W., Wallner, O., Masuyer, G., Loseva, O., Mortusewicz, O., Wiita, E., Sarno, A., Manoilov, A., Astorga-Wells, J., Jemth, A. S., Pan, L., Sanjiv, K., Karsten, S., Gokturk, C., Grube, M., Homan, E. J., Hanna, B. M. F., ... Helleday, T. (2018). Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. Science, 362(6416), 834-839. https://doi.org/10.1126/science.aar8048