Advances in Peptide-Based Chimeric Strategies for Targeted Protein Degradation

Peptide-based targeted protein degradation (TPD) has emerged as a transformative approach in drug discovery, enabling selective elimination of disease-associated proteins. This review summarizes advances in peptide-driven degradation technologies, covering ubiquitin-proteasome system-based strategies such as Peptide-based PROTACs (P-PROTACs) and hydrophobic tagging (HyT). It also highlights lysosome-targeting strategies-exemplified by lysosome-targeting chimeras (LYTACs)-that utilize the endocytosis-lysosome pathway for degrading extracellular and membrane proteins. Emerging autophagy-based approaches, including autophagosome-tethering compounds (ATTECs), further expand the degradable protein landscape. Additionally, peptide-based nanoself-assembly strategies are discussed as promising means to enhance targeting precision. The review covers fundamental principles, molecular design strategies, mechanisms, recent progress, and limitations of each platform. These innovations advance our understanding of cellular degradation pathways and offer promising therapeutic avenues for complex diseases, guiding the rational design and clinical translation of peptide-based degraders in next-generation precision medicine.