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

Torkild Visnes, Armando Cázares-Körner, Wenjing Hao, Olov Wallner, Geoffrey Masuyer, Olga Loseva, Oliver Mortusewicz, Elisée Wiita, Antonio Sarno, Aleksandr Manoilov, Juan Astorga-Wells, Ann Sofie Jemth, Lang Pan, Kumar Sanjiv, Stella Karsten, Camilla Gokturk, Maurice Grube, Evert J. Homan, Bishoy M.F. Hanna, Cynthia B.J. Paulin & 20 others Therese Pham, Azita Rasti, Ulrika Warpman Berglund, Catharina Von Nicolai, Carlos Benitez-Buelga, Tobias Koolmeister, Dag Ivanic, Petar Iliev, Martin Scobie, Hans E. Krokan, Pawel Baranczewski, Per Artursson, Mikael Altun, Annika Jenmalm Jensen, Christina Kalderén, Xueqing Ba, Roman A. Zubarev, Pål Stenmark, Istvan Boldogh, Thomas Helleday

Research output: Contribution to journalArticle

5 Citations (Scopus)

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–a–induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor kB 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.

Original languageEnglish (US)
Pages (from-to)834-839
Number of pages6
JournalScience
Volume362
Issue number6416
DOIs
StatePublished - Nov 16 2018

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DNA Glycosylases
Inflammation
Gene Expression
DNA
Guanine
DNA Repair
Reactive Oxygen Species
Catalytic Domain
Necrosis
Lung
Genes
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Visnes, T., Cázares-Körner, A., Hao, W., Wallner, O., Masuyer, G., Loseva, O., ... Helleday, T. (2018). Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. Science, 362(6416), 834-839. https://doi.org/10.1126/science.aar8048

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

In: Science, Vol. 362, No. 6416, 16.11.2018, p. 834-839.

Research output: Contribution to journalArticle

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 2018, 'Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation', Science, vol. 362, no. 6416, pp. 834-839. https://doi.org/10.1126/science.aar8048
Visnes T, Cázares-Körner A, Hao W, Wallner O, Masuyer G, Loseva O et al. Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. Science. 2018 Nov 16;362(6416):834-839. https://doi.org/10.1126/science.aar8048
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. / Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. In: Science. 2018 ; Vol. 362, No. 6416. pp. 834-839.
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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–a–induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor kB 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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T1 - Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation

AU - Visnes, Torkild

AU - Cázares-Körner, Armando

AU - Hao, Wenjing

AU - Wallner, Olov

AU - Masuyer, Geoffrey

AU - Loseva, Olga

AU - Mortusewicz, Oliver

AU - Wiita, Elisée

AU - Sarno, Antonio

AU - Manoilov, Aleksandr

AU - Astorga-Wells, Juan

AU - Jemth, Ann Sofie

AU - Pan, Lang

AU - Sanjiv, Kumar

AU - Karsten, Stella

AU - Gokturk, Camilla

AU - Grube, Maurice

AU - Homan, Evert J.

AU - Hanna, Bishoy M.F.

AU - Paulin, Cynthia B.J.

AU - Pham, Therese

AU - Rasti, Azita

AU - Berglund, Ulrika Warpman

AU - Von Nicolai, Catharina

AU - Benitez-Buelga, Carlos

AU - Koolmeister, Tobias

AU - Ivanic, Dag

AU - Iliev, Petar

AU - Scobie, Martin

AU - Krokan, Hans E.

AU - Baranczewski, Pawel

AU - Artursson, Per

AU - Altun, Mikael

AU - Jensen, Annika Jenmalm

AU - Kalderén, Christina

AU - Ba, Xueqing

AU - Zubarev, Roman A.

AU - Stenmark, Pål

AU - Boldogh, Istvan

AU - Helleday, Thomas

PY - 2018/11/16

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