School of Biology, Food and Environment, Hefei University, Hefei, 230601, P. R. China.
Institute of Advanced Technology, University of Science and Technology of China, Hefei, 230000, P. R. China.
Chem Biodivers. 2024 Nov;21(11):e202401081. doi: 10.1002/cbdv.202401081. Epub 2024 Oct 8.
The aberrant activation of NLRP3 inflammasomes is intricately linked to various inflammatory diseases. In this study, we present the discovery and optimization of a series of NLRP3 inflammasome inhibitors based on the pterostilbene skeleton. All compounds underwent screening to evaluate their inhibitory effects on LPS/Nigericin-induced IL-1β secretion and anti-cellular pyroptosis. Most compounds exhibit good biological activity and cellular safety, with compound D20 showing the most prominent activity. Preliminary mechanism studies suggest that compound D20 may affect the assembly of NLRP3 inflammasomes by targeting the NLRP3 protein, thereby inhibiting the activation of NLRP3 inflammasomes. The in vivo anti-inflammatory activity demonstrated significant therapeutic effect of compound D20 on DSS-induced acute colitis model in mice. This work has important reference significance for the development of drugs targeting NLRP3 inflammasomes.
NLRP3 炎性小体的异常激活与各种炎症性疾病密切相关。在本研究中，我们基于白藜芦醇骨架发现并优化了一系列 NLRP3 炎性小体抑制剂。所有化合物均经过筛选，以评估它们对 LPS/虎杖酸诱导的 IL-1β 分泌和抗细胞焦亡的抑制作用。大多数化合物表现出良好的生物活性和细胞安全性，其中化合物 D20 的活性最为突出。初步的机制研究表明，化合物 D20 可能通过靶向 NLRP3 蛋白影响 NLRP3 炎性小体的组装，从而抑制 NLRP3 炎性小体的激活。在体内抗炎活性研究中，化合物 D20 对 DSS 诱导的小鼠急性结肠炎模型表现出显著的治疗效果。这项工作对靶向 NLRP3 炎性小体药物的开发具有重要的参考意义。
