Inflammation driven by DNA sensors is now understood to be important to disease 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 calixarenes 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 inflammation and propose that suramin could be rapidly repurposed to meet an increasing clinical need.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193008 | PMC |
http://dx.doi.org/10.1016/j.isci.2023.106758 | DOI Listing |
iScience
May 2023
Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK.
Guang Pu Xue Yu Guang Pu Fen Xi
April 2005
Center of Analysis and Testing, Nanchang University, Nanchang, China.
The inclusion interaction of water-soluble p-(N,N-dimethylaminomethyl)-calix[8]arene with diphenylamine-4-sulfonic acid sodium salt was investigated by fluorimetric method. When diphenylamine-4-sulfonic acid sodium salt was added into the p-(N,N-dimethylaminomethyl)-calix[8]arene solution, the emission spectrum of diphenylamine-4-sulfonic acid sodium salt occurred to a blue shift with the enhancement of the fluorescent intensity. The results show that the formation of the inclusion complex of the p-(N,N-dimethylaminomethyl)-calix[8]arene with diphenylamine-4-sulfonic acid sodium salt.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!