Boron-Based Inhibitors of the NLRP3 Inflammasome

被引：101

作者：

Baldwin, Alex G. ^{[1
]}

Rivers-Auty, Jack ^{[2
]}

Daniels, Michael J. D. ^{[2
]}

White, Claire S. ^{[2
]}

Schwalbe, Carl H. ^{[3
]}

Schilling, Tom ^{[4
]}

Hammadi, Halah ^{[1
]}

Jaiyong, Panichakorn ^{[1
]}

Spencer, Nicholas G. ^{[4
]}

England, Hazel ^{[2
]}

Luheshi, Nadia M. ^{[2
,5
]}

Kadirvel, Manikandan ^{[1
]}

Lawrence, Catherine B. ^{[2
]}

Rothwell, Nancy J. ^{[2
]}

Harte, Michael K. ^{[1
]}

Bryce, Richard A. ^{[1
]}

Allan, Stuart M. ^{[2
]}

Eder, Claudia ^{[4
]}

Freeman, Sally ^{[1
]}

Brough, David ^{[2
]}

机构：

[1] Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol Med & Hlth, Div Pharm & Optometry,Sch Hlth Sci, Stopford Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England

[2] Univ Manchester, Div Neurosci & Expt Psychol, Sch Biol Sci, Fac Biol Med & Hlth,Manchester Acad Hlth Sci Ctr, AV Hill Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England

[3] Aston Univ, Sch Life & Hlth Sci, Aston Pharm Sch, Birmingham B4 7ET, W Midlands, England

[4] St Georges Univ London, Inst Infect & Immun, Cranmer Terrace, London SW17 0RE, England

[5] MedImmune Ltd, Aaron Klug Bldg,Granta Pk, Cambridge CB21 6GH, England

来源：

CELL CHEMICAL BIOLOGY | 2017年 / 24卷 / 11期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

K+ EFFLUX; CHELATE SYNTHESIS; ACTIVATION; NEK7; CA2+; TRICHLOROACETONITRILE; DEUBIQUITINATION; MACROPHAGES; IL-1-BETA; MECHANISM;

D O I：

10.1016/j.chembiol.2017.08.011

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：1321 / +

页数：20

共 59 条

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ELECTRONEGATIVITY IS THE AVERAGE ONE-ELECTRON ENERGY OF THE VALENCE-SHELL ELECTRONS IN GROUND-STATE FREE ATOMS [J].