2. Academic Validation
  3. Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation

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

  • Science. 2018 Nov 16;362(6416):834-839. doi: 10.1126/science.aar8048.
Torkild Visnes  # 1 2,  Armando Cázares-Körner  # 1,  Wenjing Hao  # 3,  Olov Wallner  # 1,  Geoffrey Masuyer 4,  Olga Loseva 1,  Oliver Mortusewicz 1,  Elisée Wiita 1,  Antonio Sarno 5 6,  Aleksandr Manoilov 7 8,  Juan Astorga-Wells 7 8,  Ann-Sofie Jemth 1,  Lang Pan 3,  Kumar Sanjiv 1,  Stella Karsten 1,  Camilla Gokturk 1,  Maurice Grube 1,  Evert J Homan 1,  Bishoy M F Hanna 1,  Cynthia B J Paulin 1,  Therese Pham 1,  Azita Rasti 1,  Ulrika Warpman Berglund 1,  Catharina von Nicolai 1,  Carlos Benitez-Buelga 1,  Tobias Koolmeister 1,  Dag Ivanic 1,  Petar Iliev 1,  Martin Scobie 1,  Hans E Krokan 5 6,  Pawel Baranczewski 7 9 10,  Per Artursson 9 10,  Mikael Altun 1,  Annika Jenmalm Jensen 11,  Christina Kalderén 1,  Xueqing Ba 3,  Roman A Zubarev 7 8 12,  Pål Stenmark 4 13,  Istvan Boldogh 14,  Thomas Helleday 15 16
Affiliations

Affiliations

  • 1 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden.
  • 2 Department of Biotechnology and Nanomedicine, SINTEF Industry, N-7465 Trondheim, Norway.
  • 3 Department of Microbiology and Immunology, Sealy Center for Molecular Medicine, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
  • 4 Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.
  • 5 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
  • 6 The Liaison Committee for Education, Research, and Innovation in Central Norway, Trondheim, Norway.
  • 7 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
  • 8 SciLifeLab, SE-17121 Solna, Sweden.
  • 9 Science for Life Laboratory Drug Discovery and Development Platform, ADME of Therapeutics Facility, Department of Pharmacy, Uppsala University, Uppsala, Sweden.
  • 10 Uppsala Drug Optimisation and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Uppsala University, Uppsala, Sweden.
  • 11 Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
  • 12 Department of Pharmacological and Technological Chemistry, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.
  • 13 Department of Experimental Medical Science, Lund University, Lund, Sweden.
  • 14 Department of Microbiology and Immunology, Sealy Center for Molecular Medicine, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. [email protected] [email protected].
  • 15 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden. [email protected] [email protected].
  • 16 Sheffield Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK.
  • # Contributed equally.
PMID: 30442810 DOI: 10.1126/science.aar8048
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.

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