Abstract Inflammation driven by DNA sensors is now understood to be central to disease pathogenesis. Here we describe new inhibitors of pathogenic DNA sensing, primarily of the inflammasome forming sensor AIM2. Molecular modelling and biochemistry has revealed potent inhibitors of AIM2 that work by binding competitively to the DNA binding site. Though less potent, these AIM2 inhibitors, 4-sulfonic calixarenes, also inhibit DNA sensors cGAS and TLR9 demonstrating a broad utility against pathogenic DNA-driven inflammatory responses. The 4-sulfonic calixarenes inhibited AIM2 dependent post-stroke T cell death, highlighting a proof of concept that the 4-sulfonic calixarenes could be effective at combatting post-stroke immunosuppression. By extension, we propose a broad utility against DNA driven inflammation in disease. Finally, we reveal that the ancient drug suramin, by virtue of its structural similarities, is an excellent inhibitor of DNA-dependent inflammation and propose that suramin could be rapidly repurposed to meet an ever increasing clinical need.

Discovery of an AIM2 inflammasome inhibitor for the treatment of DNA-driven inflammatory disease