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Improved anticancer potency by head‐to‐tail cyclization of short cationic anticancer peptides containing a lipophilic β 2,2 ‐amino acid
Author(s) -
Tørfoss Veronika,
Isaksson Johan,
Ausbacher Dominik,
Brandsdal BjørnOlav,
Flaten Gøril E.,
Anderssen Trude,
CavalcantiJacobsen Cristiane de A.,
Havelkova Martina,
Nguyen Leonard T.,
Vogel Hans J.,
Strøm Morten B.
Publication year - 2012
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.2441
Subject(s) - chemistry , cyclic peptide , peptide , cytotoxicity , amino acid , native chemical ligation , tetrapeptide , potency , biochemistry , stereochemistry , in vitro , chemical synthesis
We have recently reported a series of synthetic anticancer heptapeptides (H‐KKW β 2,2 WKK‐NH 2 ) containing a central achiral and lipophilic β 2,2 ‐amino acid that display low toxicity against non‐malignant cells and high proteolytic stability. In the present study, we have further investigated the effects of increasing the rigidity and amphipathicity of two of our lead heptapeptides by preparing a series of seven to five residue cyclic peptides containing the two most promising β 2,2 ‐amino acid derivatives as part of the central lipophilic core. The peptides were tested for anticancer activity against human Burkitt's lymphoma (Ramos cells), haemolytic activity against human red blood cells (RBC) and cytotoxicity against healthy human lung fibroblast cells (MRC‐5). The results demonstrated a considerable increase in anticancer potency following head‐to‐tail peptide cyclization, especially for the shortest derivatives lacking a tryptophan residue. High‐resolution NMR studies and molecular dynamics simulations together with an annexin‐V‐FITC and propidium iodide fluorescent assay showed that the peptides had a membrane disruptive mode of action and that the more potent peptides penetrated deeper into the lipid bilayer. The need for new anticancer drugs with novel modes of action is demanding, and development of short cyclic anticancer peptides with an overall rigidified and amphipathic structure is a promising approach to new anticancer agents. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.