Abstract
In the present study, the 26-residue amphipathic α-helical peptide A12L/A20L (Ac-KWKSFLKTFKSLKKTVLHTLLKAISS-amide) with strong anticancer activity and specificity was used as the framework to study the effects of helicity of α-helical anticancer peptides on biological activities. Helicity was systematically modulated by introducing d-amino acids to replace the original l-amino acids on the non-polar face or the polar face of the helix. Peptide helicity was measured by circular dichroism spectroscopy and was demonstrated to correlate with peptide hydrophobicity and the number of d-amino acid substitutions. Biological studies showed that strong hemolytic activity of peptides generally correlated with high hydrophobicity and helicity. Lower helicity caused the decrease of anti-HeLa activity of peptides. By introducing d-amino acids to replace the original l-amino acids on the non-polar face or the polar face of the helix, we improved the therapeutic index of A12L/A20L against HeLa cells by 9-fold and 22-fold, respectively. These results show that the helicity of anticancer peptides plays a crucial role for biological activities. This specific rational approach of peptide design could be a powerful method to improve the specificity of anticancer peptides as promising therapeutics in clinical practices.
Highlights
Cancer has become the most malignant diseases threatening human health and life [1,2]
We have systematically studied the effects of peptide hydrophobicity on the mechanism of action of α-helical cationic anticancer peptides and demonstrated peptides killed various cancer cells with a fast necrotic mechanism causing cell membrane lysis and hydrophobicity plays a crucial role during the action [11]
In order to illustrate the relationships of hydrophobicity and helicity with the biological activity of amphipathic α-helical anticancer peptides, anticancer peptide A12L/A20L was used as the parent peptide
Summary
Cancer has become the most malignant diseases threatening human health and life [1,2]. The composition difference of cell membranes between cancer cells and normal cells provides a target of designing and developing new anticancer peptide therapeutics with high specificity. We have demonstrated that the α-helical cationic anticancer peptides killed various cancer cells with a fast necrotic mechanism causing cell membrane lysis, and peptide hydrophobicity played a crucial role during the action [11]. In order to alter the peptide helicity, a series of D- and L-diastereomeric peptides were designed by introducing D-amino acids to replace the original L-amino acids of α-ACPs. By comparing the helicity and the biological activities of peptides, we illustrated the role of helicity of α-ACPs during the mechanism of action against cancer cells and optimized the anticancer activity of peptide analogs as potential anticancer therapeutics
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