Discovery of an inhibitor of DNA-driven inflammation that preferentially targets the AIM2 inflammasome

Green, Jack P.; El-Sharkawy, Lina Y.; Roth, Stefan; Zhu, Jie; Cao, Jiayu; Leach, Andrew G.; Liesz, Arthur; Freeman, Sally und Brough, David (2023): Discovery of an inhibitor of DNA-driven inflammation that preferentially targets the AIM2 inflammasome. In: iScience, Bd. 26, Nr. 5, 106758

Abstract

Inflammation driven by DNA sensors is now understood to be important to dis-ease pathogenesis. Here, we describe new inhibitors of DNA sensing, primarily of the inflammasome forming sensor AIM2. Biochemistry and molecular modeling has revealed 4-sulfonic calixarenes as potent inhibitors of AIM2 that likely work by binding competitively to the DNA-binding HIN domain. Although less potent, these AIM2 inhibitors also inhibit DNA sensors cGAS and TLR9 demonstrating a broad utility against DNA-driven inflammatory responses. The 4-sulfonic calixar-enes inhibited AIM2-dependent post-stroke T cell death, highlighting a proof of concept that the 4-sulfonic calixarenes could be effective at combating post -stroke immunosuppression. By extension, we propose a broad utility against DNA-driven inflammation in disease. Finally, we reveal that the drug suramin, by virtue of its structural similarities, is an inhibitor of DNA-dependent inflamma-tion and propose that suramin could be rapidly repurposed to meet an increasing clinical need.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198