Peptide-Mediated\nSmall Molecule Lysosome-Targeting\nChimeras for Targeted Degradation of Membrane and Intracellular Proteins

Targeted\nprotein degradation through the lysosomal pathway\nhas\nattracted increasing attention and expanded the scope of degradable\nproteins. However, the endogenous lysosomal degradation strategies\nare mainly based on antibodies or nanobodies. Effective small molecule\nlysosomal degraders are still rather rare. Herein, a new lysosomal\ndegradation approach, termed peptide-mediated small molecule lysosome-targeting\nchimeras (PSMLTACs), was developed by the incorporation of small molecule\nligands with a lysosome-sorting NPGY motif containing the cell-penetrating\npeptide. PSMLTACs were successfully applied to degrade both membrane\nand intracellular targets. In particular, the PSMLTAC strategy demonstrated\nhigher degradation efficiency on membrane target PD-L1 and intracellular\ntarget PDEδ than corresponding PROTAC degraders. Taken together,\nthis proof-of-concept provides a convenient and effective strategy\nfor targeted protein degradation.