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

DOI: 10.1126/science.aar8048

Authors: Torkild Visnes (Karolinska Institutet; SINTEF Industry) , Armando Cázares-Körner (Karolinska Institutet) , Wenjing Hao (University of Texas Medical Branch at Galveston) , Olov Wallner (Karolinska Institutet) , Geoffrey Masuyer (Stockholm University) , Olga Loseva (Karolinska Institutet) , Oliver Mortusewicz (Karolinska Institutet) , Elisée Wiita (Karolinska Institutet) , Antonio Sarno (Norwegian University of Science and Technology; The Liaison Committee for Education, Research, and Innovation in Central Norway) , Aleksandr Manoilov (Karolinska Institutet; SciLifeLab) , Juan Astorga-Wells (Karolinska Institutet; SciLifeLab) , Ann-Sofie Jemth (Karolinska Institutet) , Lang Pan (University of Texas Medical Branch at Galveston) , Kumar Sanjiv (Karolinska Institutet) , Stella Karsten (Karolinska Institutet) , Camilla Gokturk (Karolinska Institutet) , Maurice Grube (Karolinska Institutet) , Evert J. Homan (Karolinska Institutet) , Bishoy M. F. Hanna (Karolinska Institutet) , Cynthia B. J. Paulin (Karolinska Institutet) , Therese Pham (Karolinska Institutet) , Azita Rasti (Karolinska Institutet) , Ulrika Warpman Berglund (Karolinska Institutet) , Catharina Von Nicolai (Karolinska Institutet) , Carlos Benitez-Buelga (Karolinska Institutet) , Tobias Koolmeister (Karolinska Institutet) , Dag Ivanic (Karolinska Institutet) , Petar Iliev (Karolinska Institutet) , Martin Scobie (Karolinska Institutet) , Hans E. Krokan (Norwegian University of Science and Technology; 6The Liaison Committee for Education, Research, and Innovation in Central Norway) , Pawel Baranczewski (Karolinska Institutet; Uppsala University) , Per Artursson (Uppsala University) , Mikael Altun (Karolinska Institutet) , Annika Jenmalm Jensen (Karolinska Institutet) , Christina Kalderén (Karolinska Institutet) , Xueqing Ba (University of Texas Medical Branch at Galveston) , Roman A. Zubarev (Karolinska Institutet; SciLifeLab; I.M. Sechenov First Moscow State Medical University) , Pal Stenmark (Stockholm University; Lund University) , Istvan Boldogh (University of Texas Medical Branch at Galveston) , Thomas Helleday (Karolinska Institutet; University of Sheffield)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science , VOL 362 , PAGES 834 - 839

State: Published (Approved)
Published: November 2018
Diamond Proposal Number(s): 15806

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–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.

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 22/11/2018 14:22

Discipline Tags:

Health & Wellbeing Biochemistry Genetics Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)