title: Role of helicity on the anticancer mechanism of action of cationic-helical peptides.
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.
authors: Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130012, China.
authors: Yi-Bing
authors: YB
authors: Huang
authors: Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130012, China.
authors: Li-Yan
authors: LY
authors: He
authors: The First Hospital, Jilin University, Changchun 130021, China.
authors: Hong-Yu
authors: HY
authors: Jiang
authors: Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130012, China.
authors: Yu-Xin
authors: 0000-0001-6649-9324
authors: YX
authors: Chen
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D002412:Cations; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002942:Circular Dichroism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004912:Erythrocytes / Q000187:drug effects; D006367:HeLa Cells; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
chemical_list: D000596:Amino Acids; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D002412:Cations; D010455:Peptides