Chen Cuixia, Hu Jing, Yang Cheng, Zhang Yu, Wang Fang, Mu Quanmeng, Pan Fang, Xu Hai, Lu Jian Ren
Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China.
J Mater Chem B. 2016 Apr 7;4(13):2359-2368. doi: 10.1039/c6tb00155f. Epub 2016 Mar 16.
The artificially designed amphiphilic peptide G(IIKK)I-NH has been shown to be highly effective at killing bacteria and inhibiting the growth of tumor cells whilst remaining benign to normal mammalian cells. Herein we report how the side chain length and branching of constituent amino acids affect these bioactivities. Two peptide groups were designed by utilizing G(IIKK)I-NH as the base template. In Group 1, hydrophobic residues were replaced from Ile to Leu, Nle (norleucine), or Val. It was found that an increase in the side chain carbon number from 3 (Val) to 4 (Leu, Ile or Nle) substantially enhanced their antibacterial and antitumor activities, but different branching in the butyl side chain showed very different cytotoxicities to host mammalian cells, with the γ-branching in Leu eliciting the highest potency. Group 2 covered those cationic Lys residues which were replaced by synthetic homologues with shorter side chains, namely, Orn, Dab and Dap containing 3, 2 and 1 methylene units, respectively. The replacement did not affect their antibacterial activities much, but their anticancer activities were maximized in Orn and Dab. On the other hand, their cytotoxicities also became higher, indicating a multi-faceted role played by the cationic residues. Thus, changes in both the side chain length and branching strongly affected the amphiphilicity of the short peptides and their interactions with different membranes. This work has revealed a strong relationship among side chain structures, amphiphilicity and selective bioactivities of the short peptide amphiphiles.
人工设计的两亲性肽G(IIKK)I-NH已被证明在杀死细菌和抑制肿瘤细胞生长方面非常有效，同时对正常哺乳动物细胞保持良性。在此我们报告组成氨基酸的侧链长度和分支如何影响这些生物活性。以G(IIKK)I-NH为基础模板设计了两个肽组。在第1组中，疏水残基从异亮氨酸被替换为亮氨酸、正亮氨酸（正缬氨酸）或缬氨酸。发现侧链碳原子数从3（缬氨酸）增加到4（亮氨酸、异亮氨酸或正亮氨酸）可显著增强它们的抗菌和抗肿瘤活性，但丁基侧链的不同分支对宿主哺乳动物细胞表现出非常不同的细胞毒性，亮氨酸中的γ分支具有最高的效力。第2组涵盖那些被具有较短侧链的合成同系物取代的阳离子赖氨酸残基，即分别含有3、2和1个亚甲基单元的鸟氨酸、二氨基丁酸和二氨基丙酸。这种取代对它们的抗菌活性影响不大，但它们的抗癌活性在鸟氨酸和二氨基丁酸中达到最大值。另一方面，它们的细胞毒性也变得更高，表明阳离子残基发挥了多方面的作用。因此，侧链长度和分支的变化强烈影响短肽的两亲性及其与不同膜的相互作用。这项工作揭示了短肽两亲物的侧链结构、两亲性和选择性生物活性之间的密切关系。
