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<p>Targeted degradation of membrane-associated proteins, which constitute a crucial class of drug targets implicated in diverse disease pathologies, has garnered considerable attention in chemical biology and drug discovery recently. Taking advantage of the endosomal entrapment of cell-penetrating peptides (CPPs) in delivering bioactive macromolecules, we successfully construct a CPP-based platform for specific degradation of cell surface proteins by conjugation of target protein-binding small molecules (SMs) with different CPPs, resulting in the formation of CPP-mediated lysosome-targeting chimeras (CPPTACs). Through the endo-lysosomal pathway, CPPTACs exhibit a remarkable ability to degrade clinically significant plasma membrane proteins, including PD-L1, CAIX, and CB<sub>2</sub>R. In contrast to LYTACs and similar technologies, CPPTACs drive the degradation of targets in a manner independent of specific lysosome-shuttling receptors, thus providing a widely applicable strategy for plasma membrane protein degradation, regardless of the cell types. Additionally, simpler structural design and broader therapeutic window for CPPTACs are expected since CPPs-mediated endocytosis and lysosomal degradation do not necessitate the three-component binding model typically required by other heterobifunctional degraders. Overall, consisting of small molecules and biocompatible cell-penetrating peptides, CPPTACs developed in this study represent a simple, adaptable, and effective approach for selectively degrading cell surface proteins in various cellular contexts with potential for application in both biological research and therapeutic interventions.</p>

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Targeted degradation of cell surface proteins through endocytosis triggered by cell-penetrating peptide-small molecule conjugates

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月14日

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  • Wanyi He,
  • Congli Chen,
  • Jiwei Zheng,
  • Yanyan Li,
  • Huaihuai Shi,
  • Yimin Zhou,
  • Meiqing Li,
  • Ping Gong,
  • Ke Liu,
  • Ximing Shao,
  • Xiaojun Yao,
  • Hongchang Li,
  • Liang Chen,
  • Lijing Fang

摘要

Targeted degradation of membrane-associated proteins, which constitute a crucial class of drug targets implicated in diverse disease pathologies, has garnered considerable attention in chemical biology and drug discovery recently. Taking advantage of the endosomal entrapment of cell-penetrating peptides (CPPs) in delivering bioactive macromolecules, we successfully construct a CPP-based platform for specific degradation of cell surface proteins by conjugation of target protein-binding small molecules (SMs) with different CPPs, resulting in the formation of CPP-mediated lysosome-targeting chimeras (CPPTACs). Through the endo-lysosomal pathway, CPPTACs exhibit a remarkable ability to degrade clinically significant plasma membrane proteins, including PD-L1, CAIX, and CB2R. In contrast to LYTACs and similar technologies, CPPTACs drive the degradation of targets in a manner independent of specific lysosome-shuttling receptors, thus providing a widely applicable strategy for plasma membrane protein degradation, regardless of the cell types. Additionally, simpler structural design and broader therapeutic window for CPPTACs are expected since CPPs-mediated endocytosis and lysosomal degradation do not necessitate the three-component binding model typically required by other heterobifunctional degraders. Overall, consisting of small molecules and biocompatible cell-penetrating peptides, CPPTACs developed in this study represent a simple, adaptable, and effective approach for selectively degrading cell surface proteins in various cellular contexts with potential for application in both biological research and therapeutic interventions.