Ultrashort Cationic Lipopeptides and Lipopeptoids Selectively Induce Cytokine Production in Macrophages

A series of ultrashort lipopeptides and lipopeptoids were tested for their ability to induce cytokine production in macrophages. Fourteen compounds were found to strongly induce production of chemokines Groα and IL-8, with a structural bias that was absent from previous antibacterial activity investigations. Compounds based on LysGlyLys and NLysGlyNLys sequences did not induce cytokine production, whereas those based on LysLysLys and NLysNLysNLys were active only when linked to a lipid tail at least sixteen carbons long. Three lipopeptides induced high levels of IL-8 production, above that of equivalent concentrations of cathelicidin LL-37, while no compound induced production of the pro-inflammatory cytokine TNF-α at or below 100 µM. Two compounds, peptoids C16OH-NLysNLysNLys and C16OH-NHarNHarNHar, were selective for IL-8 production and did not induce TNF-α or IL-1β. These compounds may prove beneficial for in vivo treatment of infectious disease, with improved bioavailability over LL-37 due to their protease-resistant scaffold.

本研究针对一系列超短脂肽（ultrashort lipopeptides）与脂肽拟物（lipopeptoids）在巨噬细胞中诱导细胞因子产生的能力开展了测试。经筛选，共有14种化合物可强效诱导趋化因子Groα与白细胞介素8（IL-8）的产生，且其结构偏好性与既往抗菌活性研究中所观察到的特征存在显著差异。基于LysGlyLys与NLysGlyNLys序列的化合物无法诱导细胞因子产生；而基于LysLysLys与NLysNLysNLys序列的化合物，仅当连接至少含16个碳的脂酰尾时才具备活性。另有3种脂肽可诱导高水平的IL-8产生，其效果优于等浓度的抗菌肽LL-37（cathelicidin LL-37）；但在浓度为100 µM及以下时，无化合物可诱导促炎细胞因子肿瘤坏死因子-α（TNF-α）的产生。两种脂肽拟物C16OH-NLysNLysNLys与C16OH-NHarNHarNHar仅对IL-8产生具有诱导选择性，不会触发TNF-α或白细胞介素1β（IL-1β）的表达。鉴于这类化合物具备抗蛋白酶的骨架结构，其生物利用度优于LL-37，因此有望用于传染病的体内治疗。