Stapling strategy enables improvement of antitumor activity and proteolytic stability of host-defense peptide hymenochirin-1B.

Hymenochirin-1B is a cationic, amphipathic, α-helical host-defense peptide with 29 residues, which was isolated from skin secretions of the Congo clawed frog and showed potent cytotoxic activities against a range of tumor cell lines. However, the application of hymenochirin-1B as a drug is limited due to its conformational flexibility and poor proteolytic stability. In this research, a series of hydrocarbon-stapled analogs of hymenochirin-1B were designed, synthesized, and tested. Some analogs showed remarkable improvement not only in α-helicity, but also in antitumor activity and protease resistance when compared to the parent peptide. The results indicated that most stapled peptide analogues possessed improved activities against a series of tumor cells; in particular, the bicyclic stapled peptide H-10 showed promising prospects for novel anti-tumor drug development. Our data demonstrated the important impacts of the all-hydrocarbon crosslink stapling strategy on the biological activity, proteolytic stability and helicity of hymenochirin-1B.