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

作者：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 · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-62776-w · 被引用次数：17 · 研究领域：Protein Degradation and Inhibitors、Peptidase Inhibition and Analysis、RNA Interference and Gene Delivery

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 selectivel...