Action mechanism of tachyplesin I and effects of PEGylation
Action mechanism of tachyplesin I and effects of PEGylation
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DOI：
10.1016/j.bbamem.2007.01.005
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发表时间：
2007-05-01
影响因子：
3.4
通讯作者：
Matsuzaki, Katsumi
中科院分区：
文献类型：
--
作者：
Imura, Yuichi;Nishida, Minoru;Matsuzaki, Katsumi
蛋白质和肽类药物的PEG化经常用于改善体内功效。研究了中国鲎膜作用环状抗菌肽鲎素1的作用机制以及PEG化对其作用机制的影响。PEG化肽诱导钙黄绿素从蛋黄L-α-磷脂酰甘油/蛋黄L-α-磷脂酰胆碱大单层囊泡中渗漏，与亲本肽相似。这两种肽诱导脂质触发耦合泄漏和易位到双层的内小叶，表明鲎素I形成一个环形孔和PEG化没有改变膜透化的母体肽的基本机制。尽管它们对模型膜的活性相似，但肽显示出非常不同的生物活性。PEG修饰后鲎素I的细胞毒性大大降低，但抗菌活性明显减弱。我们研究了由肽诱导的内膜通透性的增强。我们的研究结果表明，外膜和肽聚糖层发挥抑制作用的PEG部分的渗透。此外，通过PEG化降低DNA结合也可能导致PEG化肽的弱活性。(c)2007 Elsevier B.V.保留所有权利。
PEGylation of protein and peptide drugs is frequently used to improve in vivo efficacy. We investigated the action mechanism of tachyplesin 1, a membrane-acting cyclic antimicrobial peptide from Tachypleus tridentatus and the effects of PEGylation on the mechanism. The PEGylated peptide induced the leakage of calcein from egg yolk L-alpha-phosphatidylglycerol/egg yolk L-alpha-phosphatidylcholine large unilamellar vesicles similarly to the parent peptide. Both peptides induced lipid flip-flop coupled to leakage and was translocated into the inner leaflet of the bilayer, indicating that tachyplesin I forms a toroidal pore and that PEGylation did not alter the basic mechanism of membrane permeabilization of the parent peptide. Despite their similar activities against model membranes, the peptides showed very different biological activities. The cytotoxicity of tachyplesin I was greatly reduced by PEGylation, although the antimicrobial activity was significantly weakened. We investigated the enhancement of the permeability of inner membranes induced by the peptides. Our results suggested that outer membranes and peptidoglycan layers play an inhibitory role in the permeation of the PEG moiety. Furthermore, a reduction in DNA binding by PEGylation may also contribute to the weak activity of the PEGylated peptide. (c) 2007 Elsevier B.V. All rights reserved.