Boron-based inhibitors of the NLRP3 inflammasome

Alex G. Baldwin, Jack Rivers-Auty, Michael J.D. Daniels, Claire S. White, Carl H. Schwalbe, Tom Schilling, Halah Hammadi, Panichakorn Jaiyong, Nicholas G. Spencer, Hazel England, Nadia M. Luheshi, Manikandan Kadirvel, Catherine B. Lawrence, Nancy J. Rothwell, Michael K. Harte, Richard A. Bryce, Stuart M. Allan, Claudia Eder, Sally Freeman, David Brough

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)

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. The NLRP3 inflammasome is known to contribute to damaging inflammation during disease. Baldwin et al. describe a new boron-containing series of inflammasome inhibitors, which may lead to the development of new anti-inflammatory molecules and allow further interrogation of inflammatory mechanisms.

Original languageEnglish
Pages (from-to)1321-1335.e5
Number of pages20
JournalCell Chemical Biology
Volume24
Issue number11
Early online date21 Sep 2017
DOIs
Publication statusPublished - 16 Nov 2017

Bibliographical note

Funding Information:
We thank Paul MacLellan and Soraya Alnabulsi for initial support with organic synthesis. Thanks to Neil O'Hara for assistance with NMR kinetic runs and the Mass Spectroscopy Service in the School of Chemistry, University of Manchester. We thank Dr P.N. Horton and Dr G.J. Tizzard of the UK National Crystallography Service, Southampton, for collection of X-ray crystallographic data. We are also grateful to Dr. Arnaud Garcon and UMIP for guidance and financial support provided to this project. Preliminary work in this project was supported by a Wellcome Trust fellowship (D.B. grant ref. no. 083482/Z/07/Z ). We are also grateful to the SBC Open Innovation Challenge. This work was also supported by the Medical Research Council Confidence in Concept scheme (grant ref. no. MC_PC_13070 ). A.G.B. is funded by the Division of Pharmacy and Optometry, University of Manchester and the Presidential Doctoral Scholar award. M.J.D.D. is funded by an MRC DTP studentship ( MR/K501311/1 ). C.B.L., J.R.-A., and D.B. are funded by the Alzheimer's Society ( 211(AS-PG-2013-2007) ). We are grateful to Dr. Vishva Dixit (Genentech) for providing the NLRP3 KO mice and to Prof. Clare Bryant (University of Cambridge) for providing the immortalized BMDMs.

Publisher Copyright:
© 2017 The Authors

Keywords

  • boron
  • inflammation
  • inhibitor
  • interleukin-1
  • NLRP3 inflammasome

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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