title: Anticancer β-hairpin peptides: membrane-induced folding triggers activity.
abstract: 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.
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland 21702, USA.
authors.forename: Chomdao
authors.initials: C
authors.lastname: Sinthuvanich
authors.forename: Ana Salomé
authors.initials: AS
authors.lastname: Veiga
authors.forename: Kshitij
authors.initials: K
authors.lastname: Gupta
authors.forename: Diana
authors.initials: D
authors.lastname: Gaspar
authors.forename: Robert
authors.initials: R
authors.lastname: Blumenthal
authors.forename: Joel P
authors.initials: JP
authors.lastname: Schneider
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D002942:Circular Dichroism; D006461:Hemolysis; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008566:Membranes / Q000378:metabolism; D008854:Microscopy, Electron / Q000379:methods; D008954:Models, Biological; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D010455:Peptides; C574293:SVS-1 peptide