Lemuel Leonidas

Abstract Aberrant activation of the NLRP3 inflammasome contributes to a wide range of chronic inflammatory disorders. Here, we investigate small-molecule inhibitors originally developed to target the DNA repair enzyme hOGG1 and demonstrate their ability to inhibit NLRP3 activation in human cells. These compounds, including TH5487 (IC50 1.62 µM in human PBMCs), reduce IL-1β secretion while increasing type I interferon responses.

Abstract The NLRP3 inflammasome plays a central role in innate immunity and is activated in response to mitochondrial dysfunction and oxidized DNA. Here, we demonstrate that repurposed small-molecule inhibitors originally developed for DNA glycosylases, TH5487 and SU0268, potently inhibit NLRP3 activation ex vivo in human Peripheral Blood Mononuclear Cells (PBMCs) with IC50 of 1.62 μM and 3.24 μM, respectively.