2. Academic Validation
  3. Peripheral Evolution of Tanshinone IIA and Cryptotanshinone for Discovery of a Potent and Specific NLRP3 Inflammasome Inhibitor

Peripheral Evolution of Tanshinone IIA and Cryptotanshinone for Discovery of a Potent and Specific NLRP3 Inflammasome Inhibitor

  • J Med Chem. 2025 Feb 13;68(3):3460-3479. doi: 10.1021/acs.jmedchem.4c02648.
Wenqi Zhu 1,  Xiaodong Bao 1,  Yuyan Yang 1,  Muqiong Xing 1,  Sijie Xiong 1,  Siyu Chen 1,  Yongxin Zhong 1,  Xueping Hu 2,  Qianrang Lu 3,  Kairong Wang 4,  Qi Ling 3,  Sunliang Cui 1 5 6
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China.
  • 2 Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao 266237, China.
  • 3 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
  • 4 School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China.
  • 5 Department of Burns and Wound Care, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
  • 6 Jinhua Institute of Zhejiang University, Jinhua 321299, China.
PMID: 39847657 DOI: 10.1021/acs.jmedchem.4c02648
Abstract

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 5m as an NLRP3 inflammasome inhibitor, and 5m 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, 5m 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.

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