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.