Anticancer β-Hairpin Peptides: Membrane-Induced Folding Triggers Activity
- 13 March 2012
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 134 (14), 6210-6217
- https://doi.org/10.1021/ja210569f
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.Keywords
This publication has 38 references indexed in Scilit:
- In search of a novel target — Phosphatidylserine exposed by non-apoptotic tumor cells and metastases of malignancies with poor treatment efficacyBiochimica et Biophysica Acta (BBA) - Biomembranes, 2011
- Phospholipids: Key Players in Apoptosis and Immune RegulationMolecules, 2009
- Folding, Self-Assembly, and Bulk Material Properties of a De Novo Designed Three-Stranded β-Sheet HydrogelBiomacromolecules, 2009
- Studies on anticancer activities of antimicrobial peptidesBiochimica et Biophysica Acta (BBA) - Biomembranes, 2008
- Cationic antimicrobial peptides as novel cytotoxic agents for cancer treatmentExpert Opinion on Investigational Drugs, 2006
- Laminated Morphology of Nontwisting β-Sheet Fibrils Constructed via Peptide Self-AssemblyJournal of the American Chemical Society, 2005
- Structure–activity relationship studies of gomesin: Importance of the disulfide bridges for conformation, bioactivities, and serum stabilityPeptide Science, 2005
- New Lytic Peptides Based on the d,l-Amphipathic Helix Motif Preferentially Kill Tumor Cells Compared to Normal CellsBiochemistry, 2003
- Aminophospholipid Asymmetry: A Matter of Life and DeathAnnual Review of Physiology, 2003
- X-Ray crystal structure of pivaloyl-D-Pro-L-Pro-L-Ala-N-methylamide; observation of a consecutive β-turn conformationJournal of the Chemical Society, Chemical Communications, 1979