Enhancement of endotoxin neutralization by coupling of a C12-alkyl chain to a lactoferricin-derived peptide
Enhancement of endotoxin neutralization by coupling of a C12-alkyl chain to a lactoferricin-derived peptide
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DOI：
10.1042/bj20041270
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发表时间：
2005-01-01
影响因子：
4.1
通讯作者：
Brandenburg, K
中科院分区：
文献类型：
--
作者：
Andrä, J;Lohner, K;Brandenburg, K
抗菌肽酰化，其模拟天然脂肽多粘菌素B的结构，增加抗微生物和内毒素中和活性。通过生物物理手段研究了乳铁蛋白衍生肽LF 11及其N-末端酰化类似物月桂基-LF 11与不同化学型细菌脂多糖（LPS Re、Ra和光滑S型）的相互作用，并与肽的生物活性相关。两种肽对LPS化学型不同的三种肠道沙门氏菌菌株表现出高的抗菌活性。月桂基-LF 11对Re-型具有高一个数量级的活性，但对Ra-和S-型细菌的活性与LF 11相当。烷基衍生肽月桂基-LF 11显示出比LF 11更强的对人单核细胞中LPS诱导的细胞因子诱导的抑制。虽然肽-LPS相互作用本质上是静电性质的，但月桂基修饰的肽显示出强疏水组分。这样的特征可以解释这样的事实，即对于LF 11，肽结合的饱和发生在比对于月桂基-LF 11低得多的肽/LPS比率下，并且对于月桂基-LF 11观察到负LPS骨架电荷的过度补偿。LF 11对LPS的凝胶-液晶相变的影响对于LPS Re是可忽略的，但对于LPS Ra明显流化。相比之下，月桂基-LF 11在两种化学型中引起胆固醇样作用，在凝胶中流化并使液晶相中的烃链硬化。这两种肽将脂质A的混合单层/非层状聚集体结构（LPS的“内毒素原理”）转化为多层结构。这些数据有助于了解肽介导的中和内毒素的机制和肽的脂质修饰的效果。
Antibacterial peptide acylation, which mimics the structure of the natural lipopeptide polymyxin B, increases antimicrobial and endotoxin-neutralizing activities. The interaction of the lactoferricin-derived peptide LF11 and its N-terminally acylated analogue, lauryl-LF11, with different chemotypes of bacterial lipopolysaccharide (LPS Re, Ra and smooth S form) was investigated by biophysical means and was related to the peptides' biological activities. Both peptides exhibit high antibacterial activity against the three strains of Salmonella enterica differing in the LPS chemotype. Lauryl-LF11 has one order of magnitude higher activity against Re-type, but activity against Ra- and S-type bacteria is comparable with that of LF11. The alkyl derivative peptide lauryl-LF11 shows a much stronger inhibition of the LPS-induced cytokine induction in human mononuclear cells than LF11. Although peptide-LPS interaction is essentially of electrostatic nature, the lauryl-modified peptide displays a strong hydrophobic component. Such a feature might then explain the fact that saturation of the peptide binding takes place at a much lower peptide/LPS ratio for LF11 than for lauryl-LF11, and that an overcompensation of the negative LPS backbone charges is observed for lauryl-LF11. The influence of LF11 on the gel-to-liquid-crystalline phase-transition of LPS is negligible for LPS Re, but clearly fluidizing for LPS Ra. In contrast, lauryl-LF11 causes a cholesterol-like effect in the two chemotypes, fluidizing in the gel and rigidifying of the hydrocarbon chains in the liquid-crystalline phase. Both peptides convert the mixed unilamellar/non-lamellar aggregate structure of lipid A, the 'endotoxic principle' of LPS, into a multilamellar one. These data contribute to the understanding of the mechanisms of the peptide-mediated neutralization of endotoxin and effect of lipid modification of peptides.