Several
cationic antimicrobial peptides (AMPs) have recently been shown to display anticancer activity via a mechanism that usually entails the disruption of
cancer cell membranes. In this work, we designed an 18-residue anticancer
peptide, SVS-1, whose mechanism of action is designed to take advantage of the aberrant
lipid composition presented on the outer leaflet of
cancer cell membranes, which makes the surface of these cells electronegative relative to the surface of noncancerous cells. SVS-1 is designed to remain unfolded and inactive in aqueous
solution but to preferentially fold at the surface of
cancer cells, adopting an amphiphilic β-hairpin structure capable of membrane disruption. Membrane-induced folding is driven by electrostatic interaction between the
peptide and the negatively charged membrane surface of
cancer cells. SVS-1 is active against a variety of
cancer cell lines such as A549 (lung
carcinoma), KB (epidermal
carcinoma), MCF-7 (
breast carcinoma), and MDA-MB-436 (
breast carcinoma). However, the cytotoxicity toward noncancerous cells having typical membrane compositions, such as HUVEC and erythrocytes, is low. CD spectroscopy, appropriately designed
peptide controls, cell-based studies,
liposome leakage assays, and electron microscopy support the intended mechanism of action, which leads to preferential killing of cancerous cells.