Peptide-Mediated Small Molecule Lysosome-Targeting Chimeras for Targeted Degradation of Membrane and Intracellular Proteins.

Targeted protein degradation through the lysosomal pathway has attracted increasing attention and expanded the scope of degradable proteins. However, the endogenous lysosomal degradation strategies are mainly based on antibodies or nanobodies. Effective small molecule lysosomal degraders are still rather rare. Herein, a new lysosomal degradation approach, termed peptide-mediated small molecule lysosome-targeting chimeras (PSMLTACs), was developed by the incorporation of small molecule ligands with a lysosome-sorting NPGY motif containing the cell-penetrating peptide. PSMLTACs were successfully applied to degrade both membrane and intracellular targets. In particular, the PSMLTAC strategy demonstrated higher degradation efficiency on membrane target PD-L1 and intracellular target PDEδ than corresponding PROTAC degraders. Taken together, this proof-of-concept provides a convenient and effective strategy for targeted protein degradation.