Author:
McMahon Emily,El-Sayed Sherihan,Green Jack,Hoyle Christopher,Fitzpatrick Lorna,Jones Emma,Corrie Eve,Kelly Rebecca L.,Challinor Mairi,Freeman Sally,Bryce Richard A.,Lawrence Catherine B.,Brough David,Kasher Paul R.
Abstract
AbstractExcessive 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 modelling, we predict that brazilin can adopt a favourable 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.
Publisher
Cold Spring Harbor Laboratory