Bifunctional Peptide Nanofibrils for Targeted Protein Degradation

Abstract Proteolysis targeting chimera (PROTAC) is a state‐of‐the‐art technology for ablating undruggable targets. A PROTAC degrader achieves targeted protein degradation (TPD) through the simultaneous binding of a protein of interest (POI) and an E3 ligase to form a ternary complex. A nanofibril‐based PROTAC strategy to form a polynary (E3) m : PROTAC : (POI) n complex has not been reported in the TPD field up to this point. A recent innovation shows that a POI ligand and E3 ligase ligand don't have to be within a fused degrader molecule. Instead, they can be recruited to cellular proximity by a self‐assembly‐driving peptide and click chemistry. The resulting nanofibrils can recruit multiple POI and E3 ligase molecules to form a polynary complex as a degradation center. The so‐called Nano‐PROTAC provides a novel approach for TPD in cancer therapy.