Department of Biotechnology and Biosciences , University of Milano-Bicocca , Piazza della Scienza, 2 , 20126 Milano , Italy.
Department of Structural & Chemical Biology , Centro de Investigaciones Biologicas, CIB-CSIC , C/Ramiro de Maeztu, 9 , 28040 Madrid , Spain.
J Med Chem. 2018 Apr 12;61(7):2895-2909. doi: 10.1021/acs.jmedchem.7b01803. Epub 2018 Mar 12.
The structure-activity relationship was investigated in a series of synthetic TLR4 antagonists formed by a glucosamine core linked to two phosphate esters and two linear carbon chains. Molecular modeling showed that the compounds with 10, 12, and 14 carbons chains are associated with higher stabilization of the MD-2/TLR4 antagonist conformation than in the case of the C16 variant. Binding experiments with human MD-2 showed that the C12 and C14 variants have higher affinity than C10, while the C16 variant did not interact with the protein. The molecules, with the exception of the C16 variant, inhibited the LPS-stimulated TLR4 signal in human and murine cells, and the antagonist potency mirrored the MD-2 affinity calculated from in vitro binding experiments. Fourier-transform infrared, nuclear magnetic resonance, and small angle X-ray scattering measurements suggested that the aggregation state in aqueous solution depends on fatty acid chain lengths and that this property can influence TLR4 activity in this series of compounds.
研究了一系列通过连接两个磷酸酯和两条线性碳链的氨基葡萄糖核心形成的合成 TLR4 拮抗剂的结构-活性关系。分子建模表明，与 C16 变体相比，具有 10、12 和 14 个碳原子链的化合物与 MD-2/TLR4 拮抗剂构象的更高稳定性相关。与人 MD-2 的结合实验表明，C12 和 C14 变体比 C10 具有更高的亲和力，而 C16 变体与该蛋白不相互作用。除了 C16 变体之外，这些分子均抑制了人源和鼠源细胞中 LPS 刺激的 TLR4 信号，并且拮抗剂效力反映了从体外结合实验计算得出的 MD-2 亲和力。傅里叶变换红外、核磁共振和小角 X 射线散射测量表明，在水溶液中的聚集状态取决于脂肪酸链长，并且该性质可以影响该系列化合物中 TLR4 的活性。
