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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-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.

Titel:	Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation.
Autor/in / Beteiligte Person:	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, AS ; Pan, L ; Sanjiv, K ; Karsten, S ; Gokturk, C ; Grube, M ; Homan, EJ ; Hanna, BMF ; Paulin, CBJ ; Pham, T ; Rasti, A ; Berglund, UW ; von Nicolai C ; Benitez-Buelga, C ; Koolmeister, T ; Ivanic, D ; Iliev, P ; Scobie, M ; Krokan, HE ; Baranczewski, P ; Artursson, P ; Altun, M ; Jensen, AJ ; Kalderén, C ; Ba, X ; Zubarev, RA ; Stenmark, P ; Boldogh, I ; Helleday, T
Zeitschrift:	Science (New York, N.Y.), Jg. 362 (2018-11-16), Heft 6416, S. 834-839
Veröffentlichung:	<Oct. 4, 1991- > : Washington, DC : American Association for the Advancement of Science ; <i>Original Publication</i>: New York, N.Y. : [s.n.] 1880-, 2018
Medientyp:	academicJournal
ISSN:	1095-9203 (electronic)
DOI:	10.1126/science.aar8048
Schlagwort:	Animals Anti-Inflammatory Agents, Non-Steroidal therapeutic use Benzimidazoles therapeutic use DNA Glycosylases metabolism DNA Repair drug effects DNA Repair genetics Enzyme Inhibitors chemistry Enzyme Inhibitors pharmacology Gene Knockout Techniques Guanine analogs & derivatives Guanine antagonists & inhibitors Guanine metabolism HEK293 Cells Humans Inflammation genetics Jurkat Cells Mice Mice, Mutant Strains NF-kappa B genetics NF-kappa B metabolism Piperidines therapeutic use Promoter Regions, Genetic Tumor Necrosis Factor-alpha pharmacology Anti-Inflammatory Agents, Non-Steroidal pharmacology Benzimidazoles pharmacology DNA Glycosylases antagonists & inhibitors Enzyme Inhibitors therapeutic use Gene Expression drug effects Inflammation drug therapy Piperidines pharmacology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Science] 2018 Nov 16; Vol. 362 (6416), pp. 834-839. MeSH Terms: Anti-Inflammatory Agents, Non-Steroidal / pharmacology ; Benzimidazoles / pharmacology ; DNA Glycosylases / antagonists & inhibitors ; Enzyme Inhibitors / therapeutic use ; Gene Expression / drug effects ; Inflammation / drug therapy ; Piperidines / *pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal / therapeutic use ; Benzimidazoles / therapeutic use ; DNA Glycosylases / metabolism ; DNA Repair / drug effects ; DNA Repair / genetics ; Enzyme Inhibitors / chemistry ; Enzyme Inhibitors / pharmacology ; Gene Knockout Techniques ; Guanine / analogs & derivatives ; Guanine / antagonists & inhibitors ; Guanine / metabolism ; HEK293 Cells ; Humans ; Inflammation / genetics ; Jurkat Cells ; Mice ; Mice, Mutant Strains ; NF-kappa B / genetics ; NF-kappa B / metabolism ; Piperidines / therapeutic use ; Promoter Regions, Genetic ; Tumor Necrosis Factor-alpha / pharmacology Comments: Comment in: Science. 2018 Nov 16;362(6416):748-749. (PMID: 30442790) ; Comment in: Nat Rev Drug Discov. 2018 Dec 28;18(1):16. (PMID: 30591718) ; Comment in: Transplantation. 2019 Jun;103(6):1071-1073. (PMID: 31246929) References: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13300-5. (PMID: 10557315) ; Nucleic Acids Res. 2001 Mar 15;29(6):1285-92. (PMID: 11238994) ; Nat Rev Immunol. 2002 Oct;2(10):725-34. (PMID: 12360211) ; J Biol Chem. 2003 Jan 17;278(3):1450-6. (PMID: 12403772) ; FASEB J. 2005 Feb;19(2):290-2. (PMID: 15677345) ; Nature. 2005 Mar 31;434(7033):612-8. (PMID: 15800616) ; Nat Chem Biol. 2006 Jul;2(7):365-6. (PMID: 16751762) ; Nat Chem Biol. 2006 Jul;2(7):348-9. (PMID: 16783334) ; Helicobacter. 2006 Oct;11(5):494-505. (PMID: 16961812) ; Nat Rev Immunol. 2006 Dec;6(12):907-18. (PMID: 17124512) ; Free Radic Biol Med. 2007 Dec 15;43(12):1616-26. (PMID: 18037127) ; Science. 2008 Jan 11;319(5860):202-6. (PMID: 18187655) ; Nat Rev Microbiol. 2010 Jan;8(1):8-14. (PMID: 19946286) ; Nucleic Acids Res. 2010 May;38(9):2878-90. (PMID: 20071746) ; Oncogene. 2010 Jun 24;29(25):3691-702. (PMID: 20418916) ; Free Radic Biol Med. 2012 Jan 15;52(2):392-401. (PMID: 22100973) ; J Biol Chem. 2012 Jun 15;287(25):20769-73. (PMID: 22568941) ; DNA Repair (Amst). 2013 Jan 1;12(1):18-26. (PMID: 23127499) ; J Immunol. 2014 Mar 1;192(5):2384-94. (PMID: 24489103) ; J Immunol. 2014 Nov 1;193(9):4643-53. (PMID: 25267977) ; Nat Immunol. 2015 Jan;16(1):27-35. (PMID: 25521682) ; ACS Chem Biol. 2015 Oct 16;10(10):2334-43. (PMID: 26218629) ; Am J Physiol Lung Cell Mol Physiol. 2015 Dec 1;309(11):L1367-75. (PMID: 26432868) ; Nat Rev Rheumatol. 2016 Jan;12(1):49-62. (PMID: 26656660) ; J Biol Chem. 2016 Dec 2;291(49):25553-25566. (PMID: 27756845) ; Free Radic Biol Med. 2017 Jun;107:258-265. (PMID: 27871818) ; Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2604-2609. (PMID: 28143930) ; J Am Chem Soc. 2017 Feb 22;139(7):2569-2572. (PMID: 28150947) ; J Am Chem Soc. 2018 Feb 14;140(6):2105-2114. (PMID: 29376367) Grant Information: P01 AI062885 United States AI NIAID NIH HHS Substance Nomenclature: 0 (7,8-dihydro-8-oxoguanine) ; 0 (Anti-Inflammatory Agents, Non-Steroidal) ; 0 (Benzimidazoles) ; 0 (Enzyme Inhibitors) ; 0 (NF-kappa B) ; 0 (Piperidines) ; 0 (TH5487) ; 0 (Tumor Necrosis Factor-alpha) ; 5Z93L87A1R (Guanine) ; EC 3.2.2.- (DNA Glycosylases) ; EC 3.2.2.- (Ogg1 protein, mouse) ; EC 3.2.2.- (oxoguanine glycosylase 1, human) Entry Date(s): Date Created: 20181117 Date Completed: 20190325 Latest Revision: 20210219 Update Code: 20240513 PubMed Central ID: PMC6645780

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