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

Acta Pharmacologica Sinica (2026)Cite this article

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.

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Fig. 1: Identification of SAC as an agonist of PRDX1.
Fig. 2: Crystal structure analysis of PRDX1C52SC83S,1-175aa in complex with SAC.
Fig. 3: Design and peroxidase activity evaluation of danshensu’s core intermediates.
Scheme 1
Fig. 4: Compound screening using PRDX1 TSA.
Scheme 2
Fig. 5: SAR summary of screened compounds.
Fig. 6: Evaluation and validation of the PRDX1 agonist LC-PDA-01 in vitro.
Fig. 7: Cellular effect of LC-PDA-01 in HEK-293T and RAW 264.7 cells.

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Acknowledgements

This work was partially supported by the National Key Research and Development Program of China (2023YFD1800102 to ZHL) and supported by the National Natural Science Foundation of China (81903538 to HZ, 82104064 to Heng Xu, 82304301 to Huan Xiong), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0830301 to CL), the Science and Technology Commission of Shanghai Municipality (22ZR1474200 to HZ, 25ZR1402556 to Heng Xu), Science and Technology Department of Guizhou Province ([2024]015), Applied Basic Research Foundation of Yunnan Province (202501BC070005), Zhongshan Municipal Bureau of Science and Technology (CXTD2023010 to CL, 2023B2030 to Huan Xiong). We are grateful to National Centre for Protein Science Shanghai (Protein Expression and Purification system) for their instrument support and technical assistance. We thank the staff from BL19U1 beamline of National Facility for Protein Science in Shanghai (NFPS) at Shanghai Synchrotron Radiation Facility, for assistance during data collection.

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Author notes

  1. These authors contributed equally: Yu-yuan Zhu, Shuang Chen, Shu-ning Zhang

Authors and Affiliations

  1. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China

    Yu-yuan Zhu, Jian-jun Liu, Zhi-hai Li & Cheng Luo

  2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Yu-yuan Zhu, Zhen-yu Wang, Xiao-min Wang, Heng Xu & Cheng Luo

  3. University of Chinese Academy of Sciences, Beijing, 100049, China

    Yu-yuan Zhu, Heng Xu & Cheng Luo

  4. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China

    Shuang Chen, Ying-shuang Zhu, Jia-yin Liang, Jian-jun Liu, Peng-fei Liu, Cheng Luo & Huan Xiong

  5. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China

    Shu-ning Zhang

  6. Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China

    Ying-shuang Zhu, Jia-yin Liang & Cheng Luo

  7. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Zhen-yu Wang & Xiao-min Wang

  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

    Wei-lie Xiao

  9. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Hao Zhang

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  1. Yu-yuan Zhu
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Contributions

CL, Huan Xiong, and HZ conceived the original hypothesis and supervised the study. YYZ, SC, SNZ and YSZ performed the study. YYZ, ZYW, XMW, ZHL and Heng Xu performed the protein purification and other biochemical experiments. SC, SNZ, YSZ, JYL, JJL, PFL and WLX synthesized the PRDX1 agonists. YYZ, SC, HengXu, HuanXiong and HZ wrote the paper. All authors read and contributed to the final manuscript.

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Correspondence to Cheng Luo, Huan Xiong or Hao Zhang.

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Zhu, Yy., Chen, S., Zhang, Sn. et al. Design and evaluation of peroxiredoxin 1 agonist based on scaffold hopping of salvianolic acids and combinatorial click chemistry. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-026-01765-1

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