Selective inhibition of the K<sup>+</sup> efflux sensitive NLRP3 pathway by Cl<sup>-</sup> channel modulation.
AuthorsSwanton, Tessa; orcid: 0000-0003-1776-080X
Beswick, James A; orcid: 0000-0002-3985-9141
de Cesco, Stephane
Davis, John B
Lawrence, Catherine B
Brough, David; orcid: 0000-0002-2250-2381
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AbstractThe 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 <i>via</i> 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 <i>in silico</i> COX docking potential, and IL-1β release inhibitory activity. Through iterative screening and rational chemical design, we established a collection of chloride channel inhibiting active lead molecules with potent activity at the canonical NLRP3 inflammasome and no activity at COX enzymes, but only in response to stimuli that activated NLRP3 by a K<sup>+</sup> efflux-dependent mechanism. This study identifies a model for the isolation and removal of unwanted off-target effects, with the enhancement of desired activity, and establishes a new chemical motif for the further development of NLRP3 inflammasome inhibitors.
CitationChemical science, volume 11, issue 43, page 11720-11728
DescriptionFrom Europe PMC via Jisc Publications Router
History: ppub 2020-10-01, epub 2020-10-12
Publication status: Published
Funder: Medical Research Council; Grant(s): MR/N029992/1, MC_PC_17172, MR/T016515/1
Funder: Alzheimer's Society; Grant(s): AS-PhD-16-002, 10
Funder: Alzheimers Research UK; Grant(s): ARUK-2015DDI-OX