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Selective Inhibition of the K+ Efflux Sensitive NLRP3 Pathway by Cl

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Selective Inhibition of the K+ Efflux Sensitive NLRP3 Pathway by Cl Chemical Science EDGE ARTICLE View Article Online View Journal | View Issue Selective inhibition of the K+ efflux sensitive NLRP3 pathway by ClÀ channel modulation† Cite this: Chem. Sci., 2020, 11, 11720 ab c c ab All publication charges for this article Tessa Swanton, ‡ James A. Beswick, ‡ Halah Hammadi, Lucy Morris, have been paid for by the Royal Society Daniel Williams,ab Stephane de Cesco,d Lina El-Sharkawy,c Shi Yu,ab Jack Green,ab of Chemistry John B. Davis,d Catherine B. Lawrence,ab David Brough ‡*ab and Sally Freeman‡*c The NLRP3 inflammasome regulates production of the pro-inflammatory cytokines interleukin-1b (IL-1b) 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-1b release inhibitory activity. Through iterative screening and rational chemical design, we established a collection Creative Commons Attribution 3.0 Unported Licence. of chloride channel inhibiting active lead molecules with potent activity at the canonical NLRP3 Received 13th July 2020 inflammasome and no activity at COX enzymes, but only in response to stimuli that activated NLRP3 by Accepted 12th October 2020 aK+ efflux-dependent mechanism. This study identifies a model for the isolation and removal of DOI: 10.1039/d0sc03828h unwanted off-target effects, with the enhancement of desired activity, and establishes a new chemical rsc.li/chemical-science motif for the further development of NLRP3 inflammasome inhibitors. Introduction inammatory cytokine precursors pro-IL-18 and pro-IL-1b into active forms that are then secreted from the cell.1 Caspase-1 also This article is licensed under a Inammation is known to contribute to the worsening of many cleaves the pore-forming protein gasdermin D (GSDMD) which diseases, and is frequently associated with the activation of the subsequently forms membrane pores causing pyroptotic cell NOD-like receptor pyrin domain-containing protein 3 (NLRP3) death.2,3 A number of inhibitors of the NLRP3 inammasome Open Access Article. Published on 12 October 2020. Downloaded 9/25/2021 5:07:12 PM. inammasome.1 NLRP3 is studied mainly in cells of the innate have been described such as CRID3/MCC950/CP-456773 which immune system such as macrophages where it responds to binds directly to NLRP3.4,5 We previously reported that fena- danger in the form of pathogen or damage-associated molec- mate NSAIDs are also able to inhibit NLRP3 inammasome ular patterns (PAMPs or DAMPs respectively). Upon sensing activation in vitro and in vivo by virtue of their ability to act on À danger NLRP3 interacts with an adaptor protein called Cl channels.6 Targeting the regulatory pathways of NLRP3 may apoptosis-associated speck-like protein containing a CARD complement strategies to inhibit the protein directly. Fenamate À (ASC) causing its oligomerisation into an activating platform for targeting of Cl channels however is complicated by their the protease caspase-1. Caspase-1 then cleaves pro- primary effects at cyclooxygenase (COX) enzymes which is associated with signicant side effects with long term use. Thus, the aim of this study was to develop the NLRP3 aDivision of Neuroscience and Experimental Psychology, School of Biological Sciences, inhibiting properties of the fenamate scaffold and deselect the Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK. COX inhibiting properties. Using cycles of iterative chemistry, E-mail: [email protected] computational modelling of COX inhibition and biological bLydia Becker Institute of Immunology and Inammation, University of Manchester, measurement of effects against the NLRP3 inammasome, we À Manchester, M13 9PT, UK have developed inhibitors that block NLRP3 via Cl channel cDivision of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, inhibition and that are devoid of activity against COX. Medicine and Health, Manchester Academic Health Science Centre, University of À Furthermore, targeting Cl channels only inhibited K+-depen- Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK. E-mail: ff [email protected] dent canonical NLRP3 activation. This o ers the advantage now dAlzheimer's Research UK Oxford Drug Discovery Institute, Target Discovery Institute, of selective NLRP3 pathway modulation in diseases which may NDM Building, Roosevelt Drive, Oxford, OX3 7FZ, UK help mitigate potentially immunosuppressive effects of † Electronic supplementary information (ESI) available. See DOI: a blanket NLRP3 inhibition. 10.1039/d0sc03828h ‡ Contributed equally. 11720 | Chem. Sci.,2020,11, 11720–11728 This journal is © The Royal Society of Chemistry 2020 View Article Online Edge Article Chemical Science Experimental containing 10% (vol/vol) FBS and 1% (vol/vol) P/S for 4 h, fol- lowed by pre-treatment with NVR compound (10 mM), NS3728 Chemistry (10 mM), MCC950 (10 mM) or vehicle (DMSO (0.5%, vol/vol), Full details of the synthesis and characterisation for all Sigma) in serum-free DMEM at indicated concentrations for compounds are provided in the ESI Chemistry le.† All other 15 min. To induce canonical NLRP3 activation, 5 mM ATP pharmacological reagents were obtained from Sigma (Niumic (Sigma) or 75 mM imiquimod (InvivoGen) was added directly to acid (NFA), Tolfenamic acid (TFA), Flufenamic acid (FFA), Clo- wells for 1 or 2 h, respectively. Alternatively, hypotonic buffer nixin, Furosemide, SB 225002, U-104, S4, Celecoxib, Mefenamic (27 mM NaCl, 0.54 mM KCl, 0.3 mM KH2PO4, 0.5 mM MgCl2, acid, Bay 11-7082, MCC950 and Ac-Tyr–Val–Ala–Asp- 0.9 mM CaCl2, 20 mM HEPES, 5 mM NaHCO3 and 3 mM À chloromethylketone (Ac-YVAD-CMK)). glucose, pH 7.4, 117 mOsm kg 1 (ref. 7)) was added to LPS- À primed (1 mgml 1; 4 h) BMDMs for 4 h pre-treated with NVR m m m Cell culture compound (10 M), NS3728 (10 M), MCC950 (10 M) or vehicle (DMSO (0.5%)) to induce NLRP3 activation. Isotonic buffer Primary BMDMs. For the preparation of primary bone (132 mM NaCl, 2.6 mM KCl, 1.4 mM KH PO , 0.5 mM MgCl , marrow derived macrophages (BMDMs), wild-type C57BL/6 2 4 2 0.9 mM CaCl2, 20 mM HEPES, 5 mM NaHCO3 and 3 mM (Charles River) mice were euthanized by rising CO , followed À 2 glucose, pH 7.4, 340 mOsm kg 1 (ref. 7)) was used as control. by cervical dislocation. All procedures were carried out in For NLRC4 or AIM2 inammasome activation, LPS-primed (1 mg accordance with the Home Office (Animals) Scientic Proce- À ml 1; 4 h) BMDMs were pre-treated with NVR compound (10 dures Act (1986). Bone marrow was isolated from the femur and mM), NS3728 (10 mM), MCC950 (10 mM), Ac-YVADCMK (100 mM) tibia bones of C57BL/6 mice and re-suspended in ACK lysis or vehicle (DMSO (0.5%)) for 15 min in serum-free DMEM and buffer (Fisher Scientic) for lysis of red blood cells. The À then transfected with either 1 mgml 1 agellin from Salmonella remaining cells were cultured in L929-containing Dulbecco's À typhimurium (Invivogen) or 1 mgml1 poly(deoxyadenylic- Modied Eagle's Medium (DMEM) with 10% (vol/vol) fetal Creative Commons Attribution 3.0 Unported Licence. À thymidylic) acid sodium salt (poly(dA:dT), Sigma), respec- bovine serum (FBS, Life Technologies), 100 U ml 1 penicillin À tively, using Lipofectamine 3000 (Thermosher) per manufac- and 100 mgml 1 streptomycin (1% P/S, Sigma). On day 6–7, cells À turer's instructions, for 4 h. For BMDM priming experiments, were scraped and seeded overnight at a density of 1 Â 106 ml 1 cells were pre-treated with NVR compound (10 mM), MCC950 (10 in 24- or 96-well plates. mM) or vehicle (DMSO (0.5%)) in serum-free DMEM for 15 min ASC-mCherry iBMDMs. Immortalised BMDMs stably À followed by 4 h treatment with 1 mgml 1 LPS. For alternative expressing ASC conjugated to mCherry6 were cultured in DMEM inammasome activation, primary human CD14+ monocytes with 10% (vol/vol) FBS and 1% (vol/vol) P/S and seeded over- À1 À were seeded and immediately treated with 1 mgml LPS in night at a density of 0.75 Â 106 ml 1 in black-walled, clear RPMI-1640 supplemented with 1% FBS, 2 mM L-glutamine and This article is licensed under a bottom 96 well plates. 1% P/S for 20 h in the presence of NVR compound (10 mM), CD14+ monocytes. Full consent from human volunteers NS3728 (10 mM), MCC950 (10 mM) or vehicle (DMSO (0.5%). (National Health Service Blood and Transplant, Manchester, UK) and ethical approval from the Research Governance, Ethics, and Open Access Article. Published on 12 October 2020. Downloaded 9/25/2021 5:07:12 PM. Integrity Committee at The University of Manchester was obtained ELISA analysis prior to experiments (ref. 2018-2696-5711). Blood was collected IL-1b, IL-6 and TNF, were analysed by ELISA according to from healthy human donors and peripheral blood mononuclear manufacturer's instructions (DuoSet, R&D Systems). cells (PBMCs) were isolated using Ficoll (Thermosher) gradient density centrifugation at 500 Â g for 40 min at room temperature. Western blot The PBMC layer was collected and platelets, plasma proteins and Lysates and/or supernatants were assessed by western blot for further contaminants were removed by washing with MACS buffer NLRP3, IL-1b, caspase-1, and GSDMD.
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