Nucleotide-binding domain leucine-rich repeat family pyrin domain containing 3 (NLRP3) inflammasome complex regulates the caspase-1 activity and subsequent processing of interleukin-1β (IL-1β). Various inflammatory diseases involve the activation of inflammasome complexes; thus, the intervention in complex formation via small molecules offers a new therapeutic opportunity. The structure-guided design and synthesis of a series of methoxystilbenes and methoxy-2-phenylnaphthalenes identified new inhibitors of NLRP3 inflammasome complex. The tetramethoxystilbene 4o and trimethoxy 2-phenylnaphthalene 1t inhibit the release of a mature form of IL-1β in J774A.1 cells with IC₅₀ values of 1.39 and 2.07 μM, respectively. Mechanistic investigation revealed that tetramethoxystilbene 4o blocks the oligomerization of apoptosis-associated speck-like protein (ASC), which is the vital step in the formation of NLRP3 inflammasome assembly, thus preventing the activation of caspase-1 and the IL-1β release. Treatment of LPS+ATP challenged mice with 20 mg/kg of 4o significantly suppressed the levels of IL-1β. The data presented herein warrant further investigation of methoxystilbenes in disease-specific models of inflammatory diseases.

中文翻译：

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四甲氧基芪通过阻断含有 Caspase 募集域的凋亡相关斑点样蛋白的寡聚化抑制 NLRP3 炎性体组装：体外和体内评估

核苷酸结合结构域富含亮氨酸的重复家族 pyrin 结构域含有 3 (NLRP3) 炎性体复合物可调节 caspase-1 活性和白细胞介素 1β (IL-1β) 的后续加工。各种炎症性疾病涉及炎症小体复合物的激活；因此，通过小分子干预复合物的形成提供了新的治疗机会。一系列甲氧基芪和甲氧基-2-苯基萘的结构引导设计和合成确定了 NLRP3 炎性体复合物的新抑制剂。四甲氧基芪 4o和三甲氧基 2-苯基萘1t抑制 J774A.1 细胞中成熟形式 IL-1β 的释放，IC ₅₀值分别为 1.39 和 2.07 μM。机理研究表明，四甲氧基芪 4o阻断凋亡相关斑点样蛋白 (ASC) 的寡聚化，这是 NLRP3 炎性体组装形成的重要步骤，从而阻止 caspase-1 的激活和 IL-1β 的释放。用 20 mg/kg 的4o处理 LPS+ATP 攻击的小鼠显着抑制了 IL-1β 的水平。本文提供的数据值得进一步研究炎症性疾病疾病特异性模型中的甲氧基芪。