Bicyclic peptide-based CPPTACs for extracellular and cell membrane protein degradation

Extracellular and cell membrane proteins are critical for maintaining physiological homeostasis and the abnormal expression of these proteins cause various diseases. Consequently, the development of targeted degradation strategy for these proteins represents a significant therapeutic opportunity. Leveraging cell-penetrating peptide (CPP)-induced endocytosis and lysosomal delivery, bicyclic CPP-mediated lysosome-targeting chimeras (CPPTACs) were developed to selectively degrade extracellular and cell surface proteins. Constructed by the conjugation of a bicyclic CPP containing the KRK motif with different target protein-binding molecules, these bicyclic peptide-based CPPTACs demonstrate the ability to enhance cellular uptake and facilitate the rapid degradation of protein targets via the endo-lysosomal pathway. These findings support the advancement of bicyclic peptide-based CPPTACs in pharmaceutical drug discovery.