Zhang Ruijia, Hong Feng, Zhao Min, Cai Xiaoying, Jiang Xueqin, Ye Neng, Su Kaiyue, Li Na, Tang Minghai, Ma Xu, Ni Hengfan, Wang Lun, Wan Li, Chen Lijuan, Wu Wenshuang, Ye Haoyu
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China.
Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
ACS Med Chem Lett. 2022 Mar 7;13(4):560-569. doi: 10.1021/acsmedchemlett.1c00597. eCollection 2022 Apr 14.
The NLRP3 inflammasome has now emerged as one of the most appealing drug targets for many inflammation-related diseases. Velutone F, a natural NLPR3 inhibitor, identified in our previous study has been limited in application by its low in planta abundance, weak activity, and complicated synthetic routes. To address these needs, structural optimization of velutone F led to a series of novel NLRP3 inhibitors. Among them, compound exerted remarkable inhibitory activity with an IC value in the nanomolar range (251.1 nM) and was approximately 5-fold more potent than velutone F. Moreover, the synthesis method of was simple, easy to handle, and scalable. Compound could suppress NLRP3 inflammasome activation by attenuating ASC speck formation. Most importantly, compound reduced peritoneal neutrophil influx in mice and IL-1β in the spleen in the MSU-induced peritonitis in LPS-primed mouse model. Taken together, compound is a prospective lead compound in the discovery of NLRP3 inflammasome inhibitors.
NLRP3炎性小体现已成为许多炎症相关疾病最具吸引力的药物靶点之一。在我们之前的研究中鉴定出的天然NLRP3抑制剂Velutone F，因其在植物中的丰度低、活性弱和合成路线复杂而在应用中受到限制。为满足这些需求，对Velutone F进行结构优化，得到了一系列新型NLRP3抑制剂。其中，化合物 表现出显著的抑制活性，IC值在纳摩尔范围内（251.1 nM），比Velutone F的效力约高5倍。此外，化合物 的合成方法简单、易于操作且可扩展。化合物 可通过减弱ASC斑点形成来抑制NLRP3炎性小体的激活。最重要的是，在LPS预处理的小鼠模型中，化合物 减少了MSU诱导的腹膜炎小鼠腹腔中性粒细胞的流入以及脾脏中IL-1β的含量。综上所述，化合物 是发现NLRP3炎性小体抑制剂的一种有前景的先导化合物。
