Issue 43, 2020

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 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+ 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.

Graphical abstract: Selective inhibition of the K+ efflux sensitive NLRP3 pathway by Cl− channel modulation

Supplementary files

Article information

Article type
Edge Article
Submitted
13 Jūl. 2020
Accepted
12 Okt. 2020
First published
12 Okt. 2020
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2020,11, 11720-11728

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

T. Swanton, J. A. Beswick, H. Hammadi, L. Morris, D. Williams, S. de Cesco, L. El-Sharkawy, S. Yu, J. Green, J. B. Davis, C. B. Lawrence, D. Brough and S. Freeman, Chem. Sci., 2020, 11, 11720 DOI: 10.1039/D0SC03828H

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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