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 -deficient mice are resistant to acute and systemic inflammation, we hypot...

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Published in:	Science (American Association for the Advancement of Science) Vol. 362; no. 6416; pp. 834 - 839
Main Authors:	Visnes, Torkild, Cázares-Körner, Armando, Hao, Wenjing, Wallner, Olov, Masuyer, Geoffrey, Loseva, Olga, Mortusewicz, Oliver, Wiita, Elisée, 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, Kalderén, Christina, Ba, Xueqing, Zubarev, Roman A, Stenmark, Pål, Boldogh, Istvan, Helleday, Thomas
Format:	Journal Article
Language:	English
Published:	United States The American Association for the Advancement of Science 16-11-2018
Subjects:	Animals Anti-Inflammatory Agents, Non-Steroidal - pharmacology Anti-Inflammatory Agents, Non-Steroidal - therapeutic use Base excision repair Basic Medicine Benzimidazoles - pharmacology Benzimidazoles - therapeutic use Binding Chromatin Deoxyribonucleic acid DNA DNA damage DNA glycosylase DNA Glycosylases - antagonists & inhibitors DNA Glycosylases - metabolism DNA repair DNA Repair - drug effects DNA Repair - genetics Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Gene expression Gene Expression - drug effects Gene Knockout Techniques Genes Guanine Guanine - analogs & derivatives Guanine - antagonists & inhibitors Guanine - metabolism HEK293 Cells Humans Immune system Immunologi inom det medicinska området Immunology in the medical area Inflammation Inflammation - drug therapy Inflammation - genetics Inhibition Inhibitors Jurkat Cells Leukocytes (neutrophilic) Lipopolysaccharides Lungs Läkemedelskemi Macromolecules Medical and Health Sciences Medicin och hälsovetenskap Medicinal Chemistry Medicinsk bioteknologi Medicinsk bioteknologi (inriktn. mot cellbiologi (inkl. stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Medicinska och farmaceutiska grundvetenskaper Mice Mice, Mutant Strains NF-kappa B - genetics NF-kappa B - metabolism OGG1 protein Oxidation resistance Piperidines - pharmacology Piperidines - therapeutic use Promoter Regions, Genetic Reactive oxygen species Repair Substrates Tumor necrosis factor Tumor Necrosis Factor-alpha - pharmacology Tumor necrosis factor-TNF Tumors
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Summary:	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 -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.
Bibliography:	Author contributions: T.V., A.C.-K., W.H., and O.W. contributed equally to this work. A.C.-K., O.W., T.K., D.I., P.I., and M.S. contributed to medicinal chemistry experiments. W.H., X.B., L.P., and I.B. designed, analyzed, and performed animal and cell culture experiments. T.V., A.C.-K., W.H., O.M., B.M.F.H., S.K., C.v.N., C.B.-B., C.K., M.A., I.B., and T.H. designed, performed, and analyzed cell biology experiments. T.V., A.C.-K., L.P., X.B., O.L., A.-S.J., A.J.J., E.W., E.J.H., C.B.J.P., M.G., and T.H. designed, performed, and analyzed biochemical and high-throughput experiments. G.M. and P.S. designed, performed, and analyzed the structural biology experiment. T.V., A.S., and H.E.K. designed, performed, and analyzed LC-MS/MS experiments. A.C.-K., A.M., J.A.-W., and R.A.Z. designed, performed, and analyzed hydrogendeuterium exchange experiments. P.B., P.A., A.C.-K., C.G., K.S., T.P., U.W.B., and A.R. designed, performed, and analyzed ADME, pharmacology, and toxicology experiments. T.V., A.C.-K., I.B., and T.H. wrote the manuscript. All authors discussed results and approved the manuscript. Present address: Department of Clinical Pharmacology, Karolinska University Hospital, SE-141 86 Stockholm, Sweden. Present address: Department of Physiology, Xiangya Medical School in Central South University, Changsha, Hunan 410078, China. Present address: Key Laboratory of Molecular Epigenetics of Ministry of Education, School of Life Science, Northeast Normal University, Changchun, Jilin 130024, China.
ISSN:	0036-8075 1095-9203 1095-9203
DOI:	10.1126/science.aar8048