Structural Modification and Antitumor Activity Study of Peptide Codesane: Discovery of Novel Stapled Peptide Antitumor Agents

The discovery of novel candidate molecules that may transform cancer treatment carries significant clinical implications. Codesane (COD), an 18-amino acid peptide extracted from the wild bee venom of Colletes daviesanus, is categorized as a cationic α-helical amphipathic antimicrobial peptide. COD, produced via solid-phase peptide synthesis, displayed significant antitumor activity in vitro. However, its application as a drug is restricted by conformational flexibility, poor serum stability, and low selectivity. This research focused on designing, synthesizing, and evaluating a series of stapled COD derivatives by all-hydrocarbon stapling strategy. Compared to the original peptide COD, several of these stapled derivatives showed significant enhancements in α-helicity, serum resistance, antitumor activity, and cell selectivity. Significantly, the stapled derivative COD-5, which possesses high helicity, good serum stability, and favorable selectivity, shows promising potential for novel antitumor drug development, whereas COD-3, characterized by high selectivity and good antitumor activity, serves as a preferred candidate for novel breast cancer therapeutic drugs. These findings provide a solid foundation for developing innovative and highly effective antitumor therapies.