Leveraging peptides for targeted protein degradation

OBJECTIVES: Targeted protein degradation (TPD) technology, with a particular emphasis on proteolysis-targeting chimeras (PROTAC), has emerged as a pivotal advancement in the field of drug discovery. However, several challenges-including the identification of suitable ligands for traditionally undruggable proteins, issues related to poor solubility and permeability, nonspecific biodistribution, and off-target toxicity-have significantly hindered their clinical translation. Peptides, recognized for their ability to serve as promising ligands for broad molecular recognition, exhibit unique potential to address these limitations in TPD applications. METHODS: Literature and related information were collected from online resources such as Google Scholar, Web of Science, PubMed, CNKI, Baidu Scholar, and X-mol. KEY FINDINGS: Recent advancements in peptide-mediated TPD have shown promise in overcoming these challenges as researchers focus on engineering highly selective peptides that enhance binding affinity for traditionally undruggable proteins while optimizing their solubility and permeability, with next-generation delivery systems also developed to reduce nonspecific biodistribution and off-target toxicity, thereby improving the therapeutic potential of peptide-based TPD approaches. CONCLUSIONS: This review summarizes recent advancements in peptide-based PROTAC development, focusing on innovative delivery strategies and methods for enhancing efficiency, while also offering insights into future prospects aimed at optimizing therapeutic precision and efficacy.