Insights into the Antimicrobial Activity and Cytotoxicity of Engineered α-Helical Peptide Amphiphiles
Insights into the Antimicrobial Activity and Cytotoxicity of Engineered α-Helical Peptide Amphiphiles
复制标题
DOI：
10.1021/acs.jmedchem.6b00922
复制
发表时间：
2016-12-22
影响因子：
7.3
通讯作者：
Bie, Xiaomei
中科院分区：
文献类型：
--
作者：
Ma, Zhi;Yang, Jing;Bie, Xiaomei
抗菌肽（Antimicrobial Peptides，AMP）是一种具有抗微生物侵袭能力的抗菌肽。然而，其不良的抗菌活性和潜在的细胞毒性仍然是其作为新型治疗剂的临床应用的障碍。为了提高抗菌肽的抗菌活性和细胞选择性，以白细胞菌素A为基础，通过精氨酸和亮氨酸取代不带电荷的亲水性氨基酸，设计了一系列两亲性多肽。在工程化肽中，肽7（WRL 3）（WLRAFRRLVRRL-ARGLRR-NH 2）对细菌细胞表现出高于红细胞和巨噬细胞的最高细胞选择性。荧光测量和显微镜观察表明，7增加了细胞膜的通透性，破坏了膜被膜的完整性，并最终导致整个细胞裂解。此外，流式细胞仪分析和亚细胞定位研究表明，7显示出对人肝癌细胞HepG 2的有效细胞毒性。总之，数据表明，这些工程化肽，特别是7，具有抗菌和/或抗肿瘤治疗的巨大前景。
Antimicrobial peptides (AMPs) have gained increasing attention, as they can overcome recurring microbial invasions. However, their poor antimicrobial activity and potential cytotoxicity remain impediments to their clinical applications as novel therapeutic agents. To enhance the antimicrobial activity and cell selectivity of AMPs, a series of amphiphilic peptides based on leucocin A were designed by substituting noncharged hydrophilic residues with arginine and leucine. Of the engineered peptides, peptide 7 (WRL3) (WLRAFRRLVRRL-ARGLRR-NH2) exhibited the highest cell selectivity toward bacterial cells over erythrocytes and macrophages. Fluorescent measurements and microscopic observations demonstrated that 7 increased cell membrane permeability and disrupted membrane envelope integrity, and eventually led to whole cell lysis. Additionally, flow cytometry analysis and subcellular localization studies revealed that 7 showed potent cytotoxicity against human hepatoma cells HepG2. In summary, the data indicate that these engineered peptides, in particular 7, have enormous promise for antibacterial and/or antitumor therapeutics.