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

Visnes, Torkild; Cázares-Körner, Armando; Hao, Wenjing; Wallner, Olov; Masuyer, Geoffrey; Loseva, Olga; Mortusewicz, Oliver; Wiita, Elisée; Sarno, Antonio and Manoilov, Aleksandr, et al. (2018) In Science 362(6416). p.834-839
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... (More)

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.

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@article{f33d9280-651e-4978-9a1c-80afce7a1ae2,
  abstract     = {<p>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.</p>},
  author       = {Visnes, Torkild and Cázares-Körner, Armando and Hao, Wenjing and Wallner, Olov and Masuyer, Geoffrey and Loseva, Olga and Mortusewicz, Oliver and Wiita, Elisée and Sarno, Antonio and Manoilov, Aleksandr and Astorga-Wells, Juan and Jemth, Ann Sofie and Pan, Lang and Sanjiv, Kumar and Karsten, Stella and Gokturk, Camilla and Grube, Maurice and Homan, Evert J. and Hanna, Bishoy M.F. and Paulin, Cynthia B.J. and Pham, Therese and Rasti, Azita and Berglund, Ulrika Warpman and Von Nicolai, Catharina and Benitez-Buelga, Carlos and Koolmeister, Tobias and Ivanic, Dag and Iliev, Petar and Scobie, Martin and Krokan, Hans E. and Baranczewski, Pawel and Artursson, Per and Altun, Mikael and Jensen, Annika Jenmalm and Kalderén, Christina and Ba, Xueqing and Zubarev, Roman A. and Stenmark, Pål and Boldogh, Istvan and Helleday, Thomas},
  issn         = {0036-8075},
  language     = {eng},
  month        = {11},
  number       = {6416},
  pages        = {834--839},
  publisher    = {American Association for the Advancement of Science},
  series       = {Science},
  title        = {Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation},
  url          = {http://dx.doi.org/10.1126/science.aar8048},
  volume       = {362},
  year         = {2018},
}