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

doi:10.1016/j.chembiol.2017.08.011

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

^*Corresponding author for this work

Chemical Engineering

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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 language	English
Pages (from-to)	1321-1335.e5
Number of pages	20
Journal	Cell Chemical Biology
Volume	24
Issue number	11
Early online date	21 Sept 2017
DOIs	https://doi.org/10.1016/j.chembiol.2017.08.011
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Baldwin, A. G., Rivers-Auty, J., Daniels, M. J. D., White, C. S., Schwalbe, C. H., Schilling, T., Hammadi, H., Jaiyong, P., Spencer, N. G., England, H., Luheshi, N. M., Kadirvel, M., Lawrence, C. B., Rothwell, N. J., Harte, M. K., Bryce, R. A., Allan, S. M., Eder, C., Freeman, S., & Brough, D. (2017). Boron-based inhibitors of the NLRP3 inflammasome. Cell Chemical Biology, 24(11), 1321-1335.e5. Advance online publication. https://doi.org/10.1016/j.chembiol.2017.08.011

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title = "Boron-based inhibitors of the NLRP3 inflammasome",

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.",

keywords = "boron, inflammation, inhibitor, interleukin-1, NLRP3 inflammasome",

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

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: {\textcopyright} 2017 The Authors",

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Baldwin, AG, Rivers-Auty, J, Daniels, MJD, White, CS, Schwalbe, CH, Schilling, T, Hammadi, H, Jaiyong, P, Spencer, NG, England, H, Luheshi, NM, Kadirvel, M, Lawrence, CB, Rothwell, NJ, Harte, MK, Bryce, RA, Allan, SM, Eder, C, Freeman, S & Brough, D 2017, 'Boron-based inhibitors of the NLRP3 inflammasome', Cell Chemical Biology, vol. 24, no. 11, pp. 1321-1335.e5. https://doi.org/10.1016/j.chembiol.2017.08.011

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AU - Baldwin, Alex G.

AU - Rivers-Auty, Jack

AU - Daniels, Michael J.D.

AU - White, Claire S.

AU - Schwalbe, Carl H.

AU - Schilling, Tom

AU - Hammadi, Halah

AU - Jaiyong, Panichakorn

AU - Spencer, Nicholas G.

AU - England, Hazel

AU - Luheshi, Nadia M.

AU - Kadirvel, Manikandan

AU - Lawrence, Catherine B.

AU - Rothwell, Nancy J.

AU - Harte, Michael K.

AU - Bryce, Richard A.

AU - Allan, Stuart M.

AU - Eder, Claudia

AU - Freeman, Sally

AU - Brough, David

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PY - 2017/11/16

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N2 - 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.

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KW - inhibitor

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Boron-based inhibitors of the NLRP3 inflammasome

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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