Boron based inhibitors of the NLRP3 inflammasome

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

doi:10.1016/j.chembiol.2017.08.011

Boron based inhibitors of the NLRP3 inflammasome

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

Research output: Contribution to journal › Article › peer-review

Abstract

NLRP3 is a receptor important for host responses to infection, yet 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, that inhibit NLRP3 inflammasome in vitro and in vivo without affecting Ca²⁺ homeostasis. The core chemical insights of this work is that oxazaborine ring is a critical feature of the NBC series, and the main biological insight that 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.

Original language	English
Pages (from-to)	1321-1335
Number of pages	15
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

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10.1016/j.chembiol.2017.08.011Licence: CC BY

Contribution of Neuro-inflammation to cerebral ischaemia
Brough, D., Allan, S., Kostarelos, K. & Rothwell, N.
31/12/15 → 30/06/19
Project: Research

CCDC 1563192: Experimental Crystal Structure Determination
Baldwin, A. (Contributor), Rivers-Auty, J. (Contributor), Daniels, M. (Contributor), White, C. (Contributor), Schwalbe, C. H. (Contributor), Schilling, T. (Contributor), Hammadi, H. (Contributor), Jaiyong, P. (Contributor), Spencer, N. G. (Contributor), England, H. (Contributor), Luheshi, N. M. (Contributor), Kadirvel, M. (Contributor), Lawrence, C. (Contributor), Rothwell, N. (Contributor), Harte, M. (Contributor), Bryce, R. (Contributor), Allan, S. M. (Contributor), Eder, C. (Contributor), Freeman, S. (Contributor) & Brough, D. (Contributor), Cambridge Crystallographic Data Centre, 1 Jan 2017
DOI: 10.5517/ccdc.csd.cc1pgmkb, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc1pgmkb&sid=DataCite
Dataset
CCDC 1563191: Experimental Crystal Structure Determination
Baldwin, A. (Contributor), Rivers-Auty, J. (Contributor), Daniels, M. (Contributor), White, C. (Contributor), Schwalbe, C. H. (Contributor), Schilling, T. (Contributor), Hammadi, H. (Contributor), Jaiyong, P. (Contributor), Spencer, N. G. (Contributor), England, H. (Contributor), Luheshi, N. M. (Contributor), Kadirvel, M. (Contributor), Lawrence, C. (Contributor), Rothwell, N. (Contributor), Harte, M. (Contributor), Bryce, R. (Contributor), Allan, S. M. (Contributor), Eder, C. (Contributor), Freeman, S. (Contributor) & Brough, D. (Contributor), Cambridge Crystallographic Data Centre, 1 Jan 2017
DOI: 10.5517/ccdc.csd.cc1pgmj9, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc1pgmj9&sid=DataCite
Dataset

Cite this

Baldwin, A., Rivers-Auty, J., Daniels, M., White, C., Schwalbe, C. H., Schilling, T., Hammadi, H., Jaiyong, P., Spencer, N. G., England, H., Luheshi, N. M., Kadirvel, M., Lawrence, C. B., Rothwell, N., Harte, M., Bryce, R., Allen, S., Eder, C., Freeman, S., & Brough, D. (2017). Boron based inhibitors of the NLRP3 inflammasome. Cell Chemical Biology, 24(11), 1321-1335. 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 also known to contribute to devastating diseases such as Alzheimer{\textquoteright}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, that inhibit NLRP3 inflammasome in vitro and in vivo without affecting Ca2+ homeostasis. The core chemical insights of this work is that oxazaborine ring is a critical feature of the NBC series, and the main biological insight that 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.",

author = "Alex Baldwin and Jack Rivers-Auty and Michael Daniels and Claire White and Schwalbe, {Carl H.} and T. 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 Nancy Rothwell and Michael Harte and Richard Bryce and Stuart Allen and Claudia Eder and Sally Freeman and David Brough",

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doi = "10.1016/j.chembiol.2017.08.011",

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

TY - JOUR

T1 - Boron based inhibitors of the NLRP3 inflammasome

AU - Baldwin, Alex

AU - Rivers-Auty, Jack

AU - Daniels, Michael

AU - White, Claire

AU - Schwalbe, Carl H.

AU - Schilling, T.

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

AU - Harte, Michael

AU - Bryce, Richard

AU - Allen, Stuart

AU - Eder, Claudia

AU - Freeman, Sally

AU - Brough, David

PY - 2017/11/16

Y1 - 2017/11/16

N2 - NLRP3 is a receptor important for host responses to infection, yet 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, that inhibit NLRP3 inflammasome in vitro and in vivo without affecting Ca2+ homeostasis. The core chemical insights of this work is that oxazaborine ring is a critical feature of the NBC series, and the main biological insight that 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.

AB - NLRP3 is a receptor important for host responses to infection, yet 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, that inhibit NLRP3 inflammasome in vitro and in vivo without affecting Ca2+ homeostasis. The core chemical insights of this work is that oxazaborine ring is a critical feature of the NBC series, and the main biological insight that 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.

U2 - 10.1016/j.chembiol.2017.08.011

DO - 10.1016/j.chembiol.2017.08.011

M3 - Article

SN - 2451-9456

VL - 24

SP - 1321

EP - 1335

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 11

ER -

Boron based inhibitors of the NLRP3 inflammasome

Abstract

Research Beacons, Institutes and Platforms

UN SDGs

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Contribution of Neuro-inflammation to cerebral ischaemia

Datasets

CCDC 1563192: Experimental Crystal Structure Determination

CCDC 1563191: Experimental Crystal Structure Determination

Cite this