Targeting clathrin-mediated endocytosis: recent advances in inhibitor development, mechanistic insights, and...

Clathrin-mediated endocytosis (CME) is a critical pathway for cellular uptake of metabolites, hormones, and pathogens, including viruses. Recent advances in understanding CME mechanisms and developing inhibitors targeting key components (clathrin, dynamin, and HSC70) have opened therapeutic avenues for diseases, such as viral infections, cancer, and neurological disorders. This review comprehensively summarizes current CME inhibitors, including Pitstop, Dynasore, and Dyngo-4a, highlighting their mechanisms, structure-activity relationships (SARs), and limitations. Small molecules like Pitstop 2 disrupt clathrin-terminal domain (TD) interactions, while dynamin inhibitors (e.g., pthaladyns and quinodyns) target GTPase or pleckstrin homology (PH) domains to block vesicle fission. Despite progress, challenges remain: many inhibitors lack specificity, exhibit cytotoxicity, or possess unclear mechanisms. Novel strategies, such as peptide-based inhibitors (e.g., Wbox2) and non-protonophoric analogs (e.g., ES9-17), demonstrate improved precision. Future research must prioritize optimizing pharmacokinetics, reducing off-target effects, and exploiting emerging targets like endocytic accessory proteins (EAPs) to advance CME inhibitors toward clinical applications.