Design and evaluation of peroxiredoxin 1 agonist based on scaffold hopping of salvianolic acids and combinatorial click chemistry

  • Acta Pharmacol Sin. 2026 Jul;47(7):1965-1979. doi: 10.1038/s41401-026-01765-1.
Yu-Yuan Zhu  #  1  2  3 ,  Shuang Chen  #  4 ,  Shu-Ning Zhang  #  5 ,  Ying-Shuang Zhu  4  6 ,  Jia-Yin Liang  4  6 ,  Zhen-Yu Wang  2  7 ,  Xiao-Min Wang  2  7 ,  Jian-Jun Liu  1  4 ,  Peng-Fei Liu  4 ,  Zhi-Hai Li  1 ,  Wei-Lie Xiao  8 ,  Heng Xu  2  3 ,  Cheng Luo  9  10  11  12  13 ,  Huan Xiong  14 ,  Hao Zhang  15
Affiliations
  • 1. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3. University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
  • 5. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.
  • 6. Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
  • 7. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 8. Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education and Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy and School of Chemical Science and Technology, Yunnan University, Kunming, 650050, China.
  • 9. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. [email protected].
  • 10. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 11. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 12. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China. [email protected].
  • 13. Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China. [email protected].
  • 14. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China. [email protected].
  • 15. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. [email protected].
  • # Contributed equally.
PMID: 41803461 DOI: 10.1038/s41401-026-01765-1
Abstract

Peroxiredoxin 1 (PRDX1) is a pivotal antioxidant enzyme maintaining intracellular Reactive Oxygen Species (ROS) balance. Deficiency of PRDX1 aggravates oxidative stress-related pathologies, whereas enhanced PRDX1 activity confers cytoprotection. Small-molecule agonists boosting PRDX1 peroxidase activity hold therapeutic promise, yet to date only two such agonists-rosmarinic acid (RA) and salvianolic acid B (SAB)-have been reported, both by our laboratory. These polyphenolic compounds are chemically rigid and recalcitrant to modification. Here, we resolved the crystal structure of PRDX1 in complex with salvianolic acid C (SAC), revealing a conserved danshensu substructure shared by SAC, RA, and SAB. Guided by this pharmacophore, we designed a scaffold hopping core structure and generated 160 derivatives via in situ click reaction. Among them, LC-PDA-01, a non-polyphenolic scaffold, exhibited the highest PRDX1 activation (EC50 = 111.8 nM). This work discloses the first structurally tractable PRDX1 agonist and highlights combinatorial click chemistry's utility in transforming natural product motifs into drug-like molecules.

Keywords
combinatorial click chemistry; peroxiredoxin 1; scaffold hopping; structurally tractable agonist.
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