Boron-Based Inhibitors of the NLRP3 Inflammasome.
Boron-Based Inhibitors of the NLRP3 Inflammasome.
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DOI：
10.1016/j.chembiol.2017.08.011
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发表时间：
2017-11-16
影响因子：
8.6
通讯作者：
Brough D
中科院分区：
文献类型：
--
作者：
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
NLRP 3是宿主对感染的反应的重要受体，但也已知有助于破坏性疾病，如阿尔茨海默病，糖尿病，动脉粥样硬化等，使得NLRP 3的抑制剂受到追捧。目前使用的抑制剂之一是2-氨基乙氧基二苯基硼酸酯（2APB）。不幸的是，除了抑制NLRP 3外，2APB还显示出对细胞Ca 2+稳态的非选择性作用。在这里，我们使用2APB作为化学支架来构建一系列抑制剂，NBC系列，其在体外和体内抑制NLRP 3炎性小体而不影响Ca 2+稳态。这项工作的核心化学见解是，恶唑硼烷环是NBC系列的关键特征，并且使用NBC抑制剂导致的主要生物学见解是NLRP 3炎性小体激活不依赖于Ca 2+。NBC化合物代表了剖析NLRP 3功能的有用工具，并且可能导致含有恶唑硼烷环的治疗剂。描述了NLRP 3炎性体的新抑制剂。NLRP 3炎性体的激活不依赖于Ca 2+。这些新的炎性体抑制剂在体内是有效的。所述抑制剂可能导致新药的开发。已知NLRP 3炎性体有助于疾病期间的破坏性炎症。Baldwin等描述了一种新的含硼系列炎性体抑制剂，这可能导致新的抗炎分子的开发，并允许进一步询问炎症机制。
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. New inhibitors of the NLRP3 inflammasome are described NLRP3 inflammasome activation is independent of Ca2+ These new inflammasome inhibitors are effective in vivo The inhibitors described may lead to the development of new drugs 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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影响因子：
16.6
作者：
Daniels MJ;Rivers-Auty J;Schilling T;Spencer NG;Watremez W;Fasolino V;Booth SJ;White CS;Baldwin AG;Freeman S;Wong R;Latta C;Yu S;Jackson J;Fischer N;Koziel V;Pillot T;Bagnall J;Allan SM;Paszek P;Galea J;Harte MK;Eder C;Lawrence CB;Brough D
通讯作者：
Brough D
影响因子：
7.3
作者：
Hawkins, Paul C. D.;Skillman, A. Geoffrey;Nicholls, Anthony
通讯作者：
Nicholls, Anthony
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
7.3
作者：
Cramer, RD
通讯作者：
Cramer, RD
影响因子：
1.7
作者：
DOROKHOV, VA;VASILEV, LS;BOGDANOV, VS
通讯作者：
BOGDANOV, VS