净电荷对螺旋型抗癌肽生物活性的影响

以高活性两亲性α-螺旋型阳离子抗癌肽A12L/A20L(多肽P)为模板, 在其亲水面进行氨基酸定点取代, 获得了一系列带有不同净电荷的多肽类似物, 研究了净电荷对螺旋型抗癌肽生物活性的影响. 结果表明, 抗癌肽净电荷的改变对其溶血活性影响较小(最大差异为2倍), 而对抗癌活性和选择性的影响显著(最大差异为10倍). 抗癌肽P的净电荷最适范围为+7到+8, 分子间静电排斥作用的最佳数目为3~5个, 高于或低于此范围, 其抗癌活性和选择性均明显降低. 与人的正常细胞相比, 负电性的癌细胞膜对于抗癌肽的净电荷变化更敏感, 表明两亲性螺旋型抗癌肽针对癌细胞与正常细胞表现出良好的选择特异性.

Effects of Net Charge on Biological Activities of Alpha-helical Anticancer Peptides

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 activitiesof cationic anticancer peptides.The results showed that there was an obvious net charge threshold amongpeptide 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.