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 inflammasomein vitroandin vivowithout 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.

中文翻译：

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NLRP3 炎性体的硼基抑制剂

NLRP3 是一种重要的受体，对宿主对感染的反应很重要，但也已知会导致阿尔茨海默病、糖尿病、动脉粥样硬化等破坏性疾病，这使得 NLRP3 抑制剂备受追捧。目前使用的抑制剂之一是 2-氨基乙氧基二苯基硼酸盐 (2APB)。不幸的是，除了抑制 NLRP3，2APB 对细胞 Ca2+ 稳态也表现出非选择性作用。在这里，我们使用 2APB 作为化学支架构建了一系列抑制剂，即 NBC 系列，它们在体外和体内抑制 NLRP3 炎性体而不影响 Ca2+ 稳态。这项工作的核心化学见解是恶氮硼环是 NBC 系列的一个关键特征，而使用 NBC 抑制剂导致的主要生物学见解是 NLRP3 炎性体激活与 Ca2+ 无关。