Selective anticancer activity of synthetic peptides derived from the host defence peptide tritrpticin.

Abstract

Antimicrobial peptides (AMPs) constitute a diverse family of peptides with the ability to protect their host against microbial infections. In addition to their ability to kill microorganisms, several AMPs also exhibit selective cytotoxicity towards cancer cells and are collectively referred to as anticancer peptides (ACPs). Here a large library of AMPs, mainly derived from the porcine cathelicidin peptide, tritrpticin (VRRFPWWWPFLRR), were assessed for their anticancer activity against the Jurkat T cell leukemia line. These anticancer potencies were compared to the cytotoxicity of the peptides towards normal cells isolated from healthy donors, namely peripheral blood mononuclear cells (PBMCs) and red blood cells (RBCs; where hemolytic activity was assessed). Among the active tritrpticin derivatives, substitution of Arg by Lys enhanced the selectivity of the peptides towards Jurkat cells when compared to PBMCs. Additionally, the side chain length of the Lys residues was also optimized to further enhance the tritrpticin ACP selectivity at low concentrations. The mechanism of action of the peptides with high selectivity involved the permeabilization of the cytoplasmic membrane of Jurkat cells, without formation of apoptotic bodies. The incorporation of non-natural Lys-based cationic amino acids could provide a new strategy to improve the selectivity of other synthetic ACPs to enhance their potential for therapeutic use against leukemia cells.

• Authors: Mauricio Arias, Evan F Haney, Ashley L Hilchie, Jennifer A Corcoran, M Eric Hyndman, Robert E W Hancock, Hans J Vogel
• Journal: Biochimica et biophysica acta. Biomembranes (Biochim Biophys Acta Biomembr) Vol. 1862 Issue 8 Pg. 183228 (08 01 2020) ISSN: 1879-2642 [Electronic] Netherlands
• PMID: 32126228 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Antimicrobial Cationic Peptides
• Antineoplastic Agents
• Oligopeptides
• Peptides
• tritrpticin
• Cathelicidins

Topics

• Animals
• Anti-Bacterial Agents (chemistry, pharmacology)
• Antimicrobial Cationic Peptides (chemistry, genetics, pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• Circular Dichroism
• Erythrocytes (drug effects)
• Escherichia coli (drug effects)
• Hemolysis (drug effects)
• Humans
• Leukocytes, Mononuclear (drug effects)
• Microbial Sensitivity Tests
• Oligopeptides (chemistry, genetics)
• Peptides (chemistry, genetics, pharmacology)
• Swine
• Cathelicidins