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Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation
Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden;SINTEF Ind, Dept Biotechnol & Nanomed, N-7465 Trondheim, Norway.ORCID iD: 0000-0003-1047-988X
Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden;Karolinska Univ Hosp, Dept Clin Pharmacol, SE-14186 Stockholm, Sweden.
Univ Texas Med Branch, Sealy Ctr Mol Med, Dept Microbiol & Immunol, Galveston, TX 77555 USA.
Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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2018 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 362, no 6416, p. 834-839Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2018. Vol. 362, no 6416, p. 834-839
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-371530DOI: 10.1126/science.aar8048ISI: 000450488500054PubMedID: 30442810OAI: oai:DiVA.org:uu-371530DiVA, id: diva2:1275644
Funder
VINNOVAEU, European Research CouncilKnut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research Swedish Research CouncilSwedish Cancer SocietySwedish Childhood Cancer FoundationRagnar Söderbergs stiftelseTorsten Söderbergs stiftelseSwedish Foundation for Strategic Research Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved

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Baranczewski, PawelArtursson, Per

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