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

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Tessa Swanton
  • Halah Hammadi
  • Lucy Morris
  • Daniel Williams
  • Stephane De Cesco
  • Lina El-sharkawy
  • Jack Green
  • John Davis

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.

Bibliographical metadata

Original languageEnglish
JournalChemical Science
Early online date12 Oct 2020
DOIs
Publication statusE-pub ahead of print - 12 Oct 2020

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