Stimulus-Responsive Conformational Transformation Of Peptide With Cell Penetrating Motif For Triggered Cytotoxicity

The KLA peptide, an antimicrobial peptide with an alpha-helical structure, needs to improve its low therapeutic efficacy and specificity for utilization as an anticancer agent. Here, we developed a modified KLA peptide (KLA-SS-R) with an intramolecular disulfide bond and a cell penetrating sequence for enhanced endocytosis and triggered cytotoxicity towards cancer cells. The intramolecular disulfide bond of KLA-SS-R sufficiently suppresses not only the helicity but also the cytotoxicity in the absence of a reducing agent. Upon treatment of KLA-SS-R to the cancer cells, the cell penetrating sequence contributes to enhanced intracellular uptake. Then, the cytoplasmic reducing agent secreted by cancer cells reduces the intramolecular disulfide bond of KLA-SS-R. Consequently, KLA-SS-R exhibits stimulus-responsive conformational transformation from low to high helicity and thereby selective cytotoxicity towards cancer cells by disruption of the plasma and mitochondrial membranes.