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

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 () and Lijing Fang ()
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Wanyi He: Chinese Academy of Sciences
Congli Chen: Chinese Academy of Sciences
Jiwei Zheng: Chinese Academy of Sciences
Yanyan Li: Chinese Academy of Sciences
Huaihuai Shi: Chinese Academy of Sciences
Yimin Zhou: Chinese Academy of Sciences
Meiqing Li: Chinese Academy of Sciences
Ping Gong: Chinese Academy of Sciences
Ke Liu: Chinese Academy of Sciences
Ximing Shao: Chinese Academy of Sciences
Xiaojun Yao: Macao Polytechnic University
Hongchang Li: Chinese Academy of Sciences
Liang Chen: Chinese Academy of Sciences
Lijing Fang: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62776-w

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