Antimicrobial and cell-penetrating properties of penetratin analogs: Effect of sequence and secondary structure
Antimicrobial and cell-penetrating properties of penetratin analogs: Effect of sequence and secondary structure
复制标题
DOI：
10.1016/j.bbamem.2012.10.010
复制
发表时间：
2013-02-01
影响因子：
3.4
通讯作者：
Nielsen, Hanne Morck
中科院分区：
文献类型：
--
作者：
Bahnsen, Jesper Soborg;Franzyk, Henrik;Nielsen, Hanne Morck
细胞穿透肽和抗菌肽分别作为药物载体和新型抗生素药物实体显示出巨大的潜力。目前的研究涉及各种肽类似物的性质，这些肽类似物来源于众所周知的CPP穿透素以及八精氨酸和不同的达特序列。在哺乳动物和细菌细胞中评估了肽长度、胍含量和非阳离子残基序列的影响。发现穿透素类似物中的精氨酸（Arg）含量影响真核细胞摄取效率、对革兰氏阳性和革兰氏阴性细菌的抗微生物活性以及真核细胞活力。所有检查的类似物保留了穿越真核细胞膜的能力，从而引起液泡器内的分布。有趣的是，一系列的改组类似物的阳离子残基在保守的位置，获得相同的α-螺旋构象天然penetratin在含有胆固醇的脂质体的存在下，而构象差异，观察到在高阴离子脂质体的存在下。虽然两组肽的抗菌作用相似，但改组类似物的真核细胞摄取明显低于天然穿透素。此外，在天然穿透素中Met到Leu的点取代对真核细胞摄取和抗菌作用没有影响，并且对细胞毒性只有轻微的影响，与改组类似物中的相同取代引起真核细胞摄取减少同时增加抗菌作用和细胞毒性的事实相反。(C)2012爱思唯尔有限公司版权所有。
Cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs) show great potential as drug delivery vectors and new antibiotic drug entities, respectively. The current study deals with the properties of a variety of peptide analogs derived from the well-known CPP penetratin as well as octaarginine and different Tat sequences. The effects of peptide length, guanidinium content, and sequence of non-cationic residues were assessed in mammalian and bacterial cells. The arginine (Arg) content in the penetratin analogs was found to influence eukaryotic cell uptake efficiency, antimicrobial activity towards both Gram-positive and Gram-negative bacteria as well as eukaryotic cell viability. All examined analogs retained the ability to cross eukaryotic membranes giving rise to a distribution within the vacuolar apparatus. Interestingly, a series of shuffled analogs of penetratin with the cationic residues in conserved positions, attain the same alpha-helical conformation as native penetratin in the presence of cholesterol-containing liposomes, while conformational differences were observed in the presence of highly anionic liposomes. While the antibacterial effect of the two groups of peptides was similar, the eukaryotic cellular uptake of the shuffled analogs was noticeably lower than for native penetratin. Moreover, a point substitution of Met to Leu in native penetratin had no influence on eukaryotic cellular uptake and antimicrobial effect, and only a minor effect on cytotoxicity, in contrast to the fact that the same substitution in the shuffled analog gave rise to reduced eukaryotic cellular uptake while increasing the antibacterial effect and cytotoxicity. (C) 2012 Elsevier B.V. All rights reserved.