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; 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

doi:10.1126/science.aar8048

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. PaulinTherese 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

Microbiology And Immunology

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	834-839
Number of pages	6
Journal	Science
Volume	362
Issue number	6416
DOIs	https://doi.org/10.1126/science.aar8048
State	Published - Nov 16 2018

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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, A. S., Pan, L., Sanjiv, K., Karsten, S., Gokturk, C., Grube, M., Homan, E. J., Hanna, B. M. F., ... 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

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

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title = "Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation",

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.",

author = "Torkild Visnes and Armando C{\'a}zares-K{\"o}rner and Wenjing Hao and Olov Wallner and Geoffrey Masuyer and Olga Loseva and Oliver Mortusewicz and Elis{\'e}e Wiita and Antonio Sarno and Aleksandr Manoilov and Juan Astorga-Wells and Jemth, {Ann Sofie} and Lang Pan and Kumar Sanjiv and Stella Karsten and Camilla Gokturk and Maurice Grube and Homan, {Evert J.} and Hanna, {Bishoy M.F.} and Paulin, {Cynthia B.J.} and Therese Pham and Azita Rasti and Berglund, {Ulrika Warpman} and {Von Nicolai}, Catharina and Carlos Benitez-Buelga and Tobias Koolmeister and Dag Ivanic and Petar Iliev and Martin Scobie and Krokan, {Hans E.} and Pawel Baranczewski and Per Artursson and Mikael Altun and Jensen, {Annika Jenmalm} and Christina Kalder{\'e}n and Xueqing Ba and Zubarev, {Roman A.} and P{\aa}l Stenmark and Istvan Boldogh and Thomas Helleday",

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doi = "10.1126/science.aar8048",

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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

Y1 - 2018/11/16

N2 - 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.

AB - 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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DO - 10.1126/science.aar8048

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AN - SCOPUS:85056608601

SN - 0036-8075

VL - 362

SP - 834

EP - 839

JO - Science

JF - Science

IS - 6416

ER -

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

Abstract

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