The NLRP3 inflammasome plays a central role in various human diseases. Despite significant interest, most clinical-grade NLRP3 inhibitors are derived from sulfonylurea inhibitor CRID3 (also called MCC950). Here, we describe a novel chemical class of NLRP3-inhibiting compounds (NIC) that exhibit potent and selective NLRP3 inflammasome inhibition in human monocytes and mouse macrophages. BRET assays demonstrate that they physically interact with NLRP3. Structural modeling further reveals they occupy the same binding site of CRID3 but in a critically different conformation. Furthermore, we show that NIC-11 and NIC-12 lack the off-target activity of CRID3 against the enzymatic activity of carbonic anhydrases I and II. NIC-12 selectively reduces circulating IL-1ß levels in the LPS-endotoxemia model in mice and inhibits NLRP3 inflammasome activation in CAPS patient monocytes and mouse macrophages with about tenfold increased potency compared with CRID3. Altogether, this study unveils a new chemical class of highly potent and selective NLRP3-targeted inhibitors with a well-defined molecular mechanism to complement existing CRID3-based NLRP3 inhibitors in pharmacological studies and serve as novel chemical leads for the development of NLRP3-targeted therapies.

中文翻译：

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新型化学型 NLRP3 抑制剂，高效靶向 CRID3 结合袋。

NLRP3炎症小体在多种人类疾病中发挥着核心作用。尽管人们对此很感兴趣，但大多数临床级 NLRP3 抑制剂均源自磺酰脲类抑制剂 CRID3（也称为 MCC950）。在这里，我们描述了一种新型化学类别的 NLRP3 抑制化合物 (NIC)，其在人单核细胞和小鼠巨噬细胞中表现出有效且选择性的 NLRP3 炎性体抑制作用。 BRET 测定表明它们与 NLRP3 发生物理相互作用。结构模型进一步揭示它们占据相同的 CRID3 结合位点，但构象截然不同。此外，我们发现 NIC-11 和 NIC-12 缺乏 CRID3 对碳酸酐酶 I 和 II 酶活性的脱靶活性。 NIC-12 选择性降低小鼠 LPS 内毒素血症模型中的循环 IL-1ß 水平，并抑制 CAPS 患者单核细胞和小鼠巨噬细胞中的 NLRP3 炎性体激活，与 CRID3 相比，效力增加约十倍。总而言之，这项研究揭示了一种新的化学类高效、选择性 NLRP3 靶向抑制剂，具有明确的分子机制，可在药理学研究中补充现有的基于 CRID3 的 NLRP3 抑制剂，并作为开发 NLRP3 靶向疗法的新化学先导物。