Abstract
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.
Highlights
Cancer is still a major threat to human health and is the second leading cause of death worldwide
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
We adopted a more comprehensive staple scanning approach, which essentially all staple positions were along the a-helical domain of hymenochirin-1B from residue 5 to 27 without replacing the conserved amino acid residues
Summary
Cancer is still a major threat to human health and is the second leading cause of death worldwide. Almost one-sixth of deaths resulted from cancer, accounting for 8.8 million globally in 2015.1 At present, the treatments of cancer are chemotherapy, radiotherapy, surgery, immunotherapy and so on,[2,3] but the overall survival rate of cancer patients still remains low. It is urgent to discover more effective agents that either inhibit the growth or induce the apoptosis of tumor cells to improve the overall survival rate of cancer patients. The native linear peptides are susceptible to proteolytic degradation, leading to the shortage of half-life period and bioavailability
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