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Boron-Based Inhibitors of the NLRP3 Inflammasome.

Baldwin, AG; Rivers-Auty, J; Daniels, MJD; White, CS; Schwalbe, CH; Schilling, T; Hammadi, H; Jaiyong, P; Spencer, NG; England, H; et al. 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 Chem Biol, 24 (11). 1321-1335.e5. ISSN 2451-9456 https://doi.org/10.1016/j.chembiol.2017.08.011
SGUL Authors: Eder, Claudia

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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.

Item Type: Article
Additional Information: © 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: NLRP3 inflammasome, boron, inflammation, inhibitor, interleukin-1, NLRP3 inflammasome, boron, inflammation, inhibitor, interleukin-1
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Cell Chem Biol
ISSN: 2451-9456
Language: eng
Dates:
DateEvent
16 November 2017Published
21 September 2017Published Online
14 August 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
083482/Z/07/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
MC_PC_13070Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/K501311/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
211(AS-PG-2013-2007)Alzheimer's SocietyUNSPECIFIED
PubMed ID: 28943355
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/109190
Publisher's version: https://doi.org/10.1016/j.chembiol.2017.08.011

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