Design, synthesis and antitumor activity of Ascaphin-8 derived stapled peptides based on halogen–sulfhydryl click chemical reactions

Ascaphin-8 (GFKDLLKGAAKALVKTVLF-NH(2)), isolated from the norepinephrine-stimulated skin secretion of the North American-tailed frog Ascaphus truei, is a C-terminal α-helical antimicrobial peptide with potential antitumor activity. However, linear peptides are difficult to be applied directly as drugs because of their inherent defects, such as low hydrolytic enzyme tolerance and poor structural stability. In this study, we designed and synthesized a series of stapled peptides based on Ascaphin-8 via thiol-halogen click chemistry. Most of the stapled peptide derivatives showed enhanced antitumor activity. Among them, A8-2-o and A8-4-Dp had the most improved structural stability, stronger hydrolytic enzyme tolerance and highest biological activity. This research may provide a reference for the stapled modification of other similar natural antimicrobial peptides.