2. Academic Validation
  3. Boron-Based Inhibitors of the NLRP3 Inflammasome

Boron-Based Inhibitors of the NLRP3 Inflammasome

  • Cell Chem Biol. 2017 Nov 16;24(11):1321-1335.e5. doi: 10.1016/j.chembiol.2017.08.011.
Alex G Baldwin 1,  Jack Rivers-Auty 2,  Michael J D Daniels 2,  Claire S White 2,  Carl H Schwalbe 3,  Tom Schilling 4,  Halah Hammadi 1,  Panichakorn Jaiyong 1,  Nicholas G Spencer 4,  Hazel England 2,  Nadia M Luheshi 5,  Manikandan Kadirvel 1,  Catherine B Lawrence 2,  Nancy J Rothwell 2,  Michael K Harte 1,  Richard A Bryce 1,  Stuart M Allan 2,  Claudia Eder 4,  Sally Freeman 6,  David Brough 7
Affiliations

Affiliations

  • 1 Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.
  • 2 Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
  • 3 Aston Pharmacy School, School of Life & Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
  • 4 St. George's, University of London, Institute for Infection and Immunity, Cranmer Terrace, London SW17 0RE, UK.
  • 5 Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK; MedImmune Ltd., Aaron Klug Building, Granta Park, Cambridge CB21 6GH, UK.
  • 6 Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK. Electronic address: [email protected].
  • 7 Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK. Electronic address: [email protected].
PMID: 28943355 DOI: 10.1016/j.chembiol.2017.08.011
Abstract

NLRP3 is a receptor important for host responses to Infection, yet is also known to contribute to devastating diseases such as Alzheimer's disease, diabetes, atherosclerosis, and Others, making inhibitors for NLRP3 sought after. One of the inhibitors currently in use is 2-aminoethoxy diphenylborinate (2APB). Unfortunately, in addition to inhibiting NLRP3, 2APB also displays non-selective effects on cellular Ca2+ homeostasis. Here, we use 2APB as a chemical scaffold to build a series of inhibitors, the NBC series, which inhibit the NLRP3 inflammasome in vitro and in vivo without affecting Ca2+ homeostasis. The core chemical insight of this work is that the oxazaborine ring is a critical feature of the NBC series, and the main biological insight the use of NBC inhibitors led to was that NLRP3 inflammasome activation was independent of Ca2+. The NBC compounds represent useful tools to dissect NLRP3 function, and may lead to oxazaborine ring-containing therapeutics.

Keywords

NLRP3 inflammasome; boron; inflammation; inhibitor; interleukin-1.

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