Development of Oligomeric Mannose-6-phosphonate Conjugates for Targeted Protein Degradation.

Lysosome targeting chimeras (LYTACs) are a new protein degradation strategy that has recently emerged. LYTACs utilize the native cell internalization process in the body to target and degrade therapeutically relevant extracellular proteins via the lysosomal pathways. The first lysosomal internalization receptor recently used for LYTACs is the mannose-6-phosphate receptor (M6PR). M6PR is expressed across most cell types, making it ideal for internalization and degradation of numerous extracellular proteins. Herein, we report the development of a series of structurally well-defined mannose-6-phosphonate (M6Pn)-peptide conjugates that are capable of linking to a variety of targeting ligands for proteins of interest and successfully internalizing and degrading those proteins through M6PR. This will greatly facilitate the development of M6Pn based LYTACs for therapeutic applications.