Design and evaluation of peroxiredoxin 1 agonist based on scaffold hopping of salvianolic acids and combinatorial click chemistry
Yu-yuan Zhu1,2,3,
Shuang Chen4,
Shu-ning Zhang5,
Ying-shuang Zhu4,6,
Jia-yin Liang4,6,
Zhen-yu Wang2,7,
Xiao-min Wang2,7,
Jian-jun Liu1,4,
Peng-fei Liu4,
Zhi-hai Li1,
Wei-lie Xiao8,
Heng Xu2,3,
Cheng Luo1,2,3,4,6,
Huan Xiong4,
Hao Zhang9
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 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Correspondence to: Cheng Luo: cluo@simm.ac.cn, Huan Xiong: xionghuan@zidd.ac.cn, Hao Zhang: zhanghao@shutcm.edu.cn,
DOI: 10.1038/s41401-026-01765-1
Received: 6 August 2025
Accepted: 26 January 2026
Advance online: 9 March 2026
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.
