Lipolanthionine peptides act as inhibitors of TLR2-mediated IL-8 secretion.: Synthesis and structure-activity relationships
Lipolanthionine peptides act as inhibitors of TLR2-mediated IL-8 secretion.: Synthesis and structure-activity relationships
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DOI：
10.1021/jm050585d
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发表时间：
2006-03-09
影响因子：
7.3
通讯作者：
Jung, G
中科院分区：
文献类型：
--
作者：
Seyberth, T;Voss, S;Jung, G
来自革兰氏阳性和阴性细菌、支原体的脂蛋白和较短的合成脂肽类似物通过Toll样受体TLR 2/TLR 1或TLR 2/TLR 6异二聚体激活先天免疫系统的细胞。由于这个原因，这些化合物构成混合或共价连接的疫苗的高活性佐剂。羊毛硫氨酸支架与脂肽的S-（2，3-二羟丙基）半胱氨酸核心结构具有结构相似性。因此，合成了基于羊毛硫氨酸的脂肽酰胺，并探测其作为潜在的TLR 2激动剂或拮抗剂的活性。当以高摩尔过量应用于激动性合成脂肽Pam（3）Cys-Ser-（LyS）（4）-OH时，分析确定的脂多糖肽酰胺的集合表现出对TLR 2介导的IL-8分泌的抑制作用。结构-活性关系揭示了两个α-碳原子的手性、所连接的脂肪酸和脂肪胺的链长以及硫原子的氧化水平对脂多糖肽酰胺的抑制活性的影响。
Lipoproteins from Gram-positive and -negative bacteria, mycoplasma, and shorter synthetic lipopeptide analogues activate cells of the innate immune system via the Toll-like receptor TLR2/TLR1 or TLR2/TLR6 heterodimers. For this reason, these compounds constitute highly active adjuvants for vaccines either admixed or covalently linked. The lanthionine scaffold has structural similarity with the S-(2,3-dihydroxypropyl)cysteine core structure of the lipopeptides. Therefore, lanthionine-based lipopeptide amides were synthesized and probed for activity as potential TLR2 agonists or antagonists. A collection of analytically defined lipolanthionine peptide amides exhibited an inhibitory effect of the TLR2-mediated IL-8 secretion when applied in high molar excess to the agonistic synthetic lipopeptide Pam(3)Cys-Ser-(LyS)(4)-OH. Structure-activity relationships revealed the influence of the chirality of the two alpha-carbon atoms, the chain lengths of the attached fatty acids and fatty amines, and the oxidation level of the sulfur atom on the inhibitory activity of the lipolanthionine peptide amides.