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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; Brough, David.
Afiliação
  • Green JP; 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.
  • El-Sharkawy LY; Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester, UK.
  • Roth S; The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, UK.
  • Zhu J; Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester M13 9PT, UK.
  • Cao J; Institute for Stroke and Dementia Research (ISD), University Hospital LMU Munich, 81377 Munich, Germany.
  • Leach AG; Institute for Stroke and Dementia Research (ISD), University Hospital LMU Munich, 81377 Munich, Germany.
  • Liesz A; Institute for Stroke and Dementia Research (ISD), University Hospital LMU Munich, 81377 Munich, Germany.
  • Freeman S; Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester M13 9PT, UK.
  • Brough D; Institute for Stroke and Dementia Research (ISD), University Hospital LMU Munich, 81377 Munich, Germany.
iScience ; 26(5): 106758, 2023 May 19.
Article em En | MEDLINE | ID: mdl-37216118
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.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article