Brazilin is a natural product inhibitor of the NLRP3 inflammasome
Emily McMahon,
Sherihan El-Sayed,
Jack Green,
Christopher Hoyle,
Lorna FitzPatrick,
Emma V. Jones,
Eve Corrie,
Rebecca L. Kelly,
Mairi Challinor,
Sally Freeman,
Richard A. Bryce,
Catherine B. Lawrence,
David Brough,
Paul R. Kasher
Affiliations
Emily McMahon
Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK; Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and the University of Manchester, Manchester M6 8HD, UK
Sherihan El-Sayed
Division of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Oxford Road M13 9PT, UK; Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
Jack Green
Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK; Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and the University of Manchester, Manchester M6 8HD, UK
Christopher Hoyle
Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK; Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and the University of Manchester, Manchester M6 8HD, UK
Lorna FitzPatrick
Medicines Discovery Catapult, Alderley Park, Macclesfield SK10 4ZF, UK
Emma V. Jones
Medicines Discovery Catapult, Alderley Park, Macclesfield SK10 4ZF, UK
Eve Corrie
Medicines Discovery Catapult, Alderley Park, Macclesfield SK10 4ZF, UK
Rebecca L. Kelly
Medicines Discovery Catapult, Alderley Park, Macclesfield SK10 4ZF, UK
Mairi Challinor
Medicines Discovery Catapult, Alderley Park, Macclesfield SK10 4ZF, UK
Sally Freeman
Division of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Oxford Road M13 9PT, UK
Richard A. Bryce
Division of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Oxford Road M13 9PT, UK
Catherine B. Lawrence
Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK; Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and the University of Manchester, Manchester M6 8HD, UK
David Brough
Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK; Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and the University of Manchester, Manchester M6 8HD, UK
Paul R. Kasher
Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK; Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and the University of Manchester, Manchester M6 8HD, UK; Corresponding author
Summary: Excessive or aberrant NLRP3 inflammasome activation has been implicated in the progression and initiation of many inflammatory conditions; however, currently no NLRP3 inflammasome inhibitors have been approved for therapeutic use in the clinic. Here we have identified that the natural product brazilin effectively inhibits both priming and activation of the NLRP3 inflammasome in cultured murine macrophages, a human iPSC microglial cell line and in a mouse model of acute peritoneal inflammation. Through computational modeling, we predict that brazilin can adopt a favorable binding pose within a site of the NLRP3 protein which is essential for its conformational activation. Our results not only encourage further evaluation of brazilin as a therapeutic agent for NLRP3-related inflammatory diseases, but also introduce this small-molecule as a promising scaffold structure for the development of derivative NLRP3 inhibitor compounds.
