Selective inhibition of the K+ efflux sensitive NLRP3 pathway by Cl− channel modulation
| Autor: | Stephane de Cesco, Daniel Williams, Lucy V Morris, Lina Y El-Sharkawy, Tessa Swanton, Halah Hammadi, Catherine B. Lawrence, Jack Peter Green, David Brough, Shi Yu, Sally Freeman, James A Beswick, John B. Davis |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification integumentary system biology Chemistry In silico Inflammasome Inflammation General Chemistry Pharmacology Inhibitory postsynaptic potential 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Enzyme Docking (molecular) Chloride channel medicine biology.protein Cyclooxygenase medicine.symptom 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Swanton, T, Beswick, J, Hammadi, H, Morris, L, Williams, D, De Cesco, S, El-sharkawy, L, Yu, S, Green, J, Davis, J, Lawrence, C, Brough, D & Freeman, S 2020, ' Selective inhibition of the K+ efflux sensitive NLRP3 pathway by Cl-channel modulation ', Chemical Science, vol. 11, no. 43, pp. 11720-11728 . https://doi.org/10.1039/D0SC03828H Chemical Science |
| ISSN: | 2041-6539 2041-6520 |
| Popis: | 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. The NLRP3 inflammasome regulates production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and contributes to inflammation exacerbating disease. |
| Databáze: | OpenAIRE |
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