Zhu Wenqi, Bao Xiaodong, Yang Yuyan, Xing Muqiong, Xiong Sijie, Chen Siyu, Zhong Yongxin, Hu Xueping, Lu Qianrang, Wang Kairong, Ling Qi, Cui Sunliang
College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China.
Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao 266237, China.
J Med Chem. 2025 Feb 13;68(3):3460-3479. doi: 10.1021/acs.jmedchem.4c02648. Epub 2025 Jan 23.
Natural products (NPs) continue to serve as an invaluable source in drug discovery, and peripheral evolution of NPs is a highly efficient evolution strategy. Herein, we describe a unified "methyl to amide" peripheral evolution of Tanshinone IIA and Cryptotanshinone for discovery of NLRP3 inflammasome inhibitors. There were 54 compounds designed and prepared, while the chemoinformatic analysis revealed that these evolved NP analogues occupy a unique chemical space. Biological evaluation identified as an NLRP3 inflammasome inhibitor, and could directly bind to the NACHT domain of the NLRP3 protein and block the interaction of NLRP3 and ASC, thus suppressing ASC oligomerization and NLRP3 inflammasome assembly. Molecular dynamic stimulations revealed that the amide moiety played a vital role in the binding mode. Moreover, exhibited therapeutical efficacy in sepsis and the NASH mouse model. In conclusion, this protocol provides a new vision of NPs' peripheral evolution and a novel NLRP3 inflammasome inhibitor.
天然产物（NPs）仍然是药物发现中宝贵的来源，NPs的外周进化是一种高效的进化策略。在此，我们描述了丹参酮IIA和隐丹参酮统一的“甲基到酰胺”外周进化，以发现NLRP3炎性小体抑制剂。共设计并制备了54种化合物，化学信息学分析表明，这些进化的NP类似物占据独特的化学空间。生物学评价确定[具体化合物名称未给出]为NLRP3炎性小体抑制剂，其可直接结合NLRP3蛋白的NACHT结构域，阻断NLRP3与ASC的相互作用，从而抑制ASC寡聚化和NLRP3炎性小体组装。分子动力学模拟表明，酰胺部分在结合模式中起关键作用。此外，[具体化合物名称未给出]在脓毒症和非酒精性脂肪性肝炎（NASH）小鼠模型中表现出治疗效果。总之，该方案为NPs的外周进化提供了新视角，并发现了一种新型NLRP3炎性小体抑制剂。
