Targeted protein degradation (TPD) technology has drawn significant attention from researchers in both academia and industry. It is rapidly evolved as a new therapeutic modality and also a useful chemical tool in selectively depleting various protein targets. As most efforts focus on cytosolic proteins using PROteolysis TArgeting Chimera (PROTAC), LYsosome TArgeting Chimera (LYTAC) recently emerged as a promising technology to deliver extracellular protein targets to lysosome for degradation through the cation-independent mannose-6-phosphate receptor (CI-M6PR). In this study, we exploited the potential of the asialoglycoprotein receptor (ASGPR), a lysosomal targeting receptor specifically expressed on liver cells, for the degradation of extracellular proteins including membrane proteins. The ligand of ASGPR, triantennary N-acetylgalactosamine (tri-GalNAc), was conjugated to biotin, antibodies, or fragments of antibodies to generate a new class of degraders. We demonstrated that the extracellular protein targets could be successfully internalized and delivered into lysosome for degradation in liver cell lines specifically by these degraders. This work will add a new dimension to TPD with cell type specificity.

中文翻译：

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作为细胞外蛋白降解剂的三触角 N-乙酰半乳糖胺缀合物的开发

靶向蛋白质降解（TPD）技术引起了学术界和工业界研究人员的高度关注。它迅速发展成为一种新的治疗方式，也是选择性消耗各种蛋白质靶点的有用化学工具。由于大多数努力都集中在使用蛋白水解靶向嵌合体 (PROTAC) 的胞质蛋白上，溶酶体靶向嵌合体 (LYTAC) 最近成为一项有前景的技术，可将细胞外蛋白靶标递送至溶酶体，通过阳离子非依赖性甘露糖 6-磷酸受体 (CI- M6PR）。在这项研究中，我们利用了脱唾液酸糖蛋白受体（ASGPR）（一种在肝细胞上特异性表达的溶酶体靶向受体）的潜力，用于降解细胞外蛋白（包括膜蛋白）。ASGPR 的配体，三触角N-乙酰半乳糖胺 (tri-GalNAc)，与生物素、抗体或抗体片段缀合，产生一类新的降解剂。我们证明，细胞外蛋白质靶点可以成功地内化并递送到溶酶体中，以在肝细胞系中通过这些降解剂进行降解。这项工作将为具有细胞类型特异性的 TPD 添加新的维度。