Abstract：
The aberrant activation of NLRP3 inflammasome has been observed in various human diseases. Targeting the NLRP3 protein with small molecule inhibitors shows immense potential as an effective strategy for disease intervention. Herein, a series of novel biphenyl-sulfonamide NLRP3 inflammasome inhibitors were designed and synthesized. The representative compound H28 was identified as potent and specific NLRP3 inflammasome inhibitor with IC50 values of 0.57 μM. Preliminary mechanistic studies have revealed that compound H28 exhibits direct binding to the NLRP3 protein (KD: 1.15 μM), effectively inhibiting the assembly and activation of the NLRP3 inflammasome. The results in a mouse acute peritonitis model revealed that H28 effectively inhibit the NLRP3 inflammasome pathway, demonstrating their anti-inflammatory properties. Our findings strongly support the further development of H28 as potential lead compound for treating NLRP3-related diseases.
摘要：
已在各种人类疾病中观察到NLRP3炎性体的异常激活。用小分子抑制剂靶向NLRP3蛋白显示出作为疾病干预的有效策略的巨大潜力。在这里，设计并合成了一系列新型联苯磺酰胺NLRP3炎性体抑制剂。代表性化合物H28被鉴定为有效且特异性的NLRP3炎性体抑制剂,IC50值为0.57μM。初步机制研究表明，化合物H28表现出与NLRP3蛋白（KD：1.15μM）的直接结合，有效抑制NLRP3炎性体的组装和激活。在小鼠急性腹膜炎模型中的结果表明，H28有效抑制NLRP3炎性体通路，证明了它们的抗炎特性。我们的发现强烈支持H28作为治疗NLRP3相关疾病的潜在先导化合物的进一步发展。
