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

被引：168

作者：

Visnes, Torkild ^{[1
,2
]}

Cazares-Korner, Armando ^{[1
,14
]}

Hao, Wenjing ^{[3
]}

Wallner, Olov ^{[1
]}

Masuyer, Geoffrey ^{[4
]}

Loseva, Olga ^{[1
]}

Mortusewicz, Oliver ^{[1
]}

Wiita, Elisee ^{[1
]}

Sarno, Antonio ^{[5
,6
]}

Manoilov, Aleksandr ^{[7
,8
]}

Astorga-Wells, Juan ^{[7
,8
]}

Jemth, Ann-Sofie ^{[1
]}

Pan, Lang ^{[3
,15
]}

Sanjiv, Kumar ^{[1
]}

Karsten, Stella ^{[1
]}

Gokturk, Camilla ^{[1
]}

Grube, Maurice ^{[1
]}

Homan, Evert J. ^{[1
]}

Hanna, Bishoy M. F. ^{[1
]}

Paulin, Cynthia B. J. ^{[1
]}

Pham, Therese ^{[1
]}

Rasti, Azita ^{[1
]}

Berglund, Ulrika Warpman ^{[1
]}

von Nicolai, Catharina ^{[1
]}

Benitez-Buelga, Carlos ^{[1
]}

Koolmeister, Tobias ^{[1
]}

Ivanic, Dag ^{[1
]}

Iliev, Petar ^{[1
]}

Scobie, Martin ^{[1
]}

Krokan, Hans E. ^{[5
,6
]}

Baranczewski, Pawel ^{[7
,9
,10
]}

Artursson, Per ^{[9
,10
]}

Altun, Mikael ^{[1
]}

Jensen, Annika Jenmalm ^{[11
]}

Kalderen, Christina ^{[1
]}

Ba, Xueqing ^{[3
,16
]}

Zubarev, Roman A. ^{[7
,8
,12
]}

Stenmark, Pal ^{[4
,13
]}

Boldogh, Istvan ^{[3
]}

Helleday, Thomas ^{[1
]}

机构：

[1] Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden

[2] SINTEF Ind, Dept Biotechnol & Nanomed, N-7465 Trondheim, Norway

[3] Univ Texas Med Branch, Sealy Ctr Mol Med, Dept Microbiol & Immunol, Galveston, TX 77555 USA

[4] Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden

[5] Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway

[6] Liaison Comm Educ Res & Innovat Cent Norway, Trondheim, Norway

[7] Karolinska Inst, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden

[8] SciLifeLab, SE-17121 Solna, Sweden

[9] Uppsala Univ, Dept Pharm, ADME Therapeut Facil, Sci Life Lab Drug Discovery & Dev Platform, Uppsala, Sweden

[10] Uppsala Univ, Dept Pharm, Uppsala Drug Optimisat & Pharmaceut Profiling Pla, Uppsala, Sweden

[11] Karolinska Inst, Chem Biol Consortium Sweden, Sci Life Lab, Div Translat Med & Chem Biol,Dept Med Biochem & B, S-17121 Stockholm, Sweden

[12] IM Sechenov First Moscow State Med Univ, Dept Pharmacol & Technol Chem, Moscow, Russia

[13] Lund Univ, Dept Expt Med Sci, Lund, Sweden

[14] Karolinska Univ Hosp, Dept Clin Pharmacol, SE-14186 Stockholm, Sweden

[15] Cent S Univ, Xiangya Med Sch, Dept Physiol, Changsha 410078, Hunan, Peoples R China

[16] Northeast Normal Univ, Sch Life Sci, Minist Educ, Key Lab Mol Epigenet, Changchun 130024, Jilin, Peoples R China

来源：

SCIENCE | 2018年 / 362卷 / 6416期

基金：

瑞典研究理事会; 欧洲研究理事会;

关键词：

OXIDATIVE DNA-DAMAGE; 8-OXOGUANINE-DNA GLYCOSYLASE; BASE MODIFICATIONS; REPAIR ENZYME; CELLS; TRANSCRIPTION; SITE; DEMETHYLATION; SPECIFICITY; DEFICIENCY;

D O I：

10.1126/science.aar8048

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：834 / +

页数：71

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