Selective inhibition of the K⁺ efflux sensitive NLRP3 pathway by Cl^- channel modulation.

ABSTRACT: The NLRP3 inflammasome regulates production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and contributes to inflammation exacerbating disease. Fenamate non-steroidal anti-inflammatory drugs (NSAIDs) were recently described as NLRP3 inflammasome inhibitors via chloride channel inhibition. Fenamate NSAIDs inhibit cyclooxygenase (COX) enzymes, limiting their potential as therapeutics for NLRP3-associated diseases due to established side effects. The aim here was to develop properties of the fenamates that inhibit NLRP3, and at the same time to reduce COX inhibition. We synthesised a library of analogues, with feedback from in silico COX docking potential, and IL-1β release inhibitory activity. Through iterative screening and rational chemical design, we es

SUBMITTER: Swanton T 

PROVIDER: S-EPMC8162947 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature