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<p>The activation of conventional (α) and novel (δ) protein kinase C (PKC) isoforms promotes lysosomal biogenesis, a critical process for clearance of pathogenic protein aggregates including β-amyloid (Aβ) and phosphorylated Tau (p-Tau) in neurodegenerative disorders. Notably, PKC activators HEP14/15, characterized by 20-methyl moiety, fail to establish classical C1B domain pharmacophore interactions, suggesting a non-canonical activation mechanism. In this study, structural diversification of 20-deoxyingenol through esterification and acetonide protection yielded 18 new derivatives (<b>2–19</b>). Systematic screening revealed their lysosome-promoting activities, with structure–activity relationship analysis identifying compounds <b>4</b> and <b>18</b> as superior autophagy inducers. At 20&#xa0;μM, these derivatives enhanced autophagic flux by 2.45-fold and 2.31-fold versus vehicle control. Moreover, compounds <b>4</b> and <b>18</b> exhibited a dose-dependent increase in lysosome numbers, promoted TFEB nuclear translocation, and enhanced lysosome-mediated lipid droplet clearance. Western blot analysis further revealed that compounds <b>4/18</b> upregulated proteins associated with the autophagy-lysosome system, suggesting their potential as promising autophagy inducers. Mechanistically, molecular docking simulations indicated thier&#xa0;high-affinity binding to PKCδ, which may explain&#xa0;their autophagy-enhancing properties.</p> Graphical Abstract <p></p>

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Design of 20-deoxyingenol-esters-based PKC agonists and their lysosome biogenesis-enhancing activity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月10日

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  • Jia-Jia Wan,
  • Qiu-Yuan Yin,
  • Mao Sun,
  • Cui-Shan Zhang,
  • Hao-Jing Zang,
  • Pei-Tong Yao,
  • Ming-Rui Yuan,
  • Ding-Kang Chen,
  • Feng Guo,
  • Qun Chen,
  • Bo-Wen Ouyang,
  • Zi-Fei Xu,
  • Ming-Ming Cao,
  • Chong-Lin Yang,
  • Xiao-Jiang Hao,
  • Ying-Tong Di

摘要

The activation of conventional (α) and novel (δ) protein kinase C (PKC) isoforms promotes lysosomal biogenesis, a critical process for clearance of pathogenic protein aggregates including β-amyloid (Aβ) and phosphorylated Tau (p-Tau) in neurodegenerative disorders. Notably, PKC activators HEP14/15, characterized by 20-methyl moiety, fail to establish classical C1B domain pharmacophore interactions, suggesting a non-canonical activation mechanism. In this study, structural diversification of 20-deoxyingenol through esterification and acetonide protection yielded 18 new derivatives (2–19). Systematic screening revealed their lysosome-promoting activities, with structure–activity relationship analysis identifying compounds 4 and 18 as superior autophagy inducers. At 20 μM, these derivatives enhanced autophagic flux by 2.45-fold and 2.31-fold versus vehicle control. Moreover, compounds 4 and 18 exhibited a dose-dependent increase in lysosome numbers, promoted TFEB nuclear translocation, and enhanced lysosome-mediated lipid droplet clearance. Western blot analysis further revealed that compounds 4/18 upregulated proteins associated with the autophagy-lysosome system, suggesting their potential as promising autophagy inducers. Mechanistically, molecular docking simulations indicated thier high-affinity binding to PKCδ, which may explain their autophagy-enhancing properties.

Graphical Abstract