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

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 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.

Source: ScienceNOW - November 15, 2018 Category: Science Authors: Visnes, T., Cazares-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. Tags: Chemistry, Immunology reports Source Type: news