Peptide-Based PROTACs: Transitioning from Static Paradigm to a Dynamic Landscape within Targeted Protein Degradation

Proteolysis-targeting chimeras (PROTACs) are becoming a powerful therapeutic strategy, enabling event-driven elimination of disease-causing proteins. While small-molecule PROTACs have advanced rapidly, their broader application is constrained by limited target scope, dependence on druggable binding pockets, and susceptibility to the hook effect. Peptide-based PROTACs (pPROTACs) have gained attention as a complementary platform, leveraging the specificity, modularity, and structural adaptability of conjugates to expand the range of degradable targets, including proteins traditionally considered undruggable. This review summarizes recent advances in classical pPROTAC design and conjugation strategies and highlights emerging nonclassic and deconstructive pPROTAC architectures that reassemble functional modules through supramolecular or genetic approaches. Further, bioPROTAC, as a protein-based degrader enabled by genetic encodability, is discussed. Together, these strategies position pPROTACs as an evolving class of targeted protein degradation agents that complement small-molecule approaches.