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Structure–Activity Relationship in Monosaccharide-Based Toll-Like Receptor 4 (TLR4) Antagonists
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-01 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01803 Fabio A. Facchini 1 , Lenny Zaffaroni 1 , Alberto Minotti 1 , Silvia Rapisarda 1 , Valentina Calabrese 1 , Matilde Forcella 1 , Paola Fusi 1 , Cristina Airoldi 1 , Carlotta Ciaramelli 1 , Jean-Marc Billod 2 , Andra B. Schromm 3 , Harald Braun 4 , Charys Palmer 5 , Rudi Beyaert 4 , Fabio Lapenta 6 , Roman Jerala 6 , Grisha Pirianov 5 , Sonsoles Martin-Santamaria 2 , Francesco Peri 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-01 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01803 Fabio A. Facchini 1 , Lenny Zaffaroni 1 , Alberto Minotti 1 , Silvia Rapisarda 1 , Valentina Calabrese 1 , Matilde Forcella 1 , Paola Fusi 1 , Cristina Airoldi 1 , Carlotta Ciaramelli 1 , Jean-Marc Billod 2 , Andra B. Schromm 3 , Harald Braun 4 , Charys Palmer 5 , Rudi Beyaert 4 , Fabio Lapenta 6 , Roman Jerala 6 , Grisha Pirianov 5 , Sonsoles Martin-Santamaria 2 , Francesco Peri 1
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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.
中文翻译：
基于单糖的收费样受体4（TLR4）拮抗剂的结构-活性关系。
在一系列合成的TLR4拮抗剂中研究了结构-活性关系，该拮抗剂由连接至两个磷酸酯和两个线性碳链的葡糖胺核心形成。分子模型表明，与C16变体相比，具有10、12和14个碳链的化合物与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变体不与蛋白质相互作用。除C16变体外，这些分子均抑制人和鼠细胞中LPS刺激的TLR4信号，并且拮抗剂的功效反映了从体外计算得出的MD-2亲和力绑定实验。傅里叶变换红外光谱，核磁共振和小角度X射线散射测量表明，水溶液中的聚集状态取决于脂肪酸链的长度，并且该性质会影响该系列化合物中的TLR4活性。
更新日期：2018-03-01
中文翻译：
基于单糖的收费样受体4（TLR4）拮抗剂的结构-活性关系。
在一系列合成的TLR4拮抗剂中研究了结构-活性关系，该拮抗剂由连接至两个磷酸酯和两个线性碳链的葡糖胺核心形成。分子模型表明，与C16变体相比，具有10、12和14个碳链的化合物与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变体不与蛋白质相互作用。除C16变体外，这些分子均抑制人和鼠细胞中LPS刺激的TLR4信号，并且拮抗剂的功效反映了从体外计算得出的MD-2亲和力绑定实验。傅里叶变换红外光谱，核磁共振和小角度X射线散射测量表明，水溶液中的聚集状态取决于脂肪酸链的长度，并且该性质会影响该系列化合物中的TLR4活性。
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