Development of Triantennary N-Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins

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