Abstract: Owing to the low possibility of induction of resistance, amphipathic α-helical anticancer peptides whose sole target is the biomembrane show their promising potentials in cancer treatments. Obtained in the previous study, an amphipathic α-helical anticancer peptide A12L/A20L(Peptide P) with significant anticancer activity was utilized as the framework to systematically design a series of peptide analogs with different net charges by amino acid substitutions on the polar face, and to study the effects of net charge on biological activities of cationic anticancer peptides. The results showed that there was an obvious net charge threshold among peptide analogs, that was the net charge of +7 to +8 and the number of electrostatic repulsion of 3—5. Increases or decreases of net charges beyond the threshold value resulted in a dramatic reduction in both anticancer activity and therapeutic index. The alteration on net charges of peptides exhibited weak effect on hemolytic activity(maximum 2-fold) but significant influence on anticancer activity and therapeutic index(maximum 10-fold), respectively. Compared with the neutral membrane of human normal cells, the negatively charged membrane of cancer cells was much more sensitive to net charge alteration of the anticancer peptide. The amphipathic α-helical anticancer peptides showed good specificity between cancer cells and human normal cells, which might play a crucial role in making further improvement in target selectivity and designing anticancer peptide agents as therapeutics with higher efficacy and lower toxicity.

Key words: Anticancer peptide, Net charge, Hydrophobicity, Hemolytic activity, Anticancer activity