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<p>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, <b>LC-PDA-01</b>, a non-polyphenolic scaffold, exhibited the highest PRDX1 activation (EC<sub>50</sub> = 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.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2026年3月9日

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  • Yu-yuan Zhu,
  • Shuang Chen,
  • Shu-ning Zhang,
  • Ying-shuang Zhu,
  • Jia-yin Liang,
  • Zhen-yu Wang,
  • Xiao-min Wang,
  • Jian-jun Liu,
  • Peng-fei Liu,
  • Zhi-hai Li,
  • Wei-lie Xiao,
  • Heng Xu,
  • Cheng Luo,
  • Huan Xiong,
  • Hao Zhang

摘要

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.