Structure-Activity Relationship in Monosaccharide-Based Toll-Like Receptor 4 (TLR4) Antagonists

被引：49

作者：

Facchini, Fabio A. ^{[1
]}

Zaffaroni, Lenny ^{[1
]}

Minotti, Alberto ^{[1
]}

Rapisarda, Silvia ^{[1
]}

Calabrese, Valentina ^{[1
]}

Forcella, Matilde ^{[1
]}

Fusi, Paola ^{[1
]}

Airoldi, Cristina ^{[1
]}

Ciaramelli, Carlotta ^{[1
]}

Billod, Jean-Marc ^{[2
]}

Schromm, Andra B. ^{[3
]}

Braun, Harald ^{[4
]}

Palmer, Charys ^{[5
]}

Beyaert, Rudi ^{[4
]}

Lapenta, Fabio ^{[6
]}

Jerala, Roman ^{[6
]}

Pirianov, Grisha ^{[5
]}

Martin-Santamaria, Sonsoles ^{[2
]}

Peri, Francesco ^{[1
]}

机构：

[1] Univ Milano Bicocca, Dept Biotechnol & Biosci, Piazza Sci 2, I-20126 Milan, Italy

[2] CSIC, Dept Struct & Chem Biol, CIB, C Ramiro de Maeztu 9, Madrid 28040, Spain

[3] Res Ctr Borstel, Div Immunobiophys, Pk Allee 1-40, D-23845 Borstel, Germany

[4] VIB UGent Ctr Inflammat Res, UGent Dept Biomed Mol Biol, Unit Mol Signal Transduct Inflammat, B-9052 Ghent, Belgium

[5] Anglia Ruskin Cambridge Univ, Cambridge CB1 1PT, England

[6] Natl Inst Chem, Kemijski Inst, Dept Synthet Biol & Immunol, Hajdrihova 19, SI-1000 Ljubljana, Slovenia

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 07期

基金：

欧盟地平线“2020”;

关键词：

N-LINKED GLYCOSYLATIONS; LIPID-A ANALOGS; CELL ACTIVATION; SEVERE SEPSIS; MD-2; ENDOTOXIN; ERITORAN; BINDING; CD14;

D O I：

10.1021/acs.jmedchem.7b01803

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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.

引用

页码：2895 / 2909

页数：15

共 48 条

[1]

Inhibition of toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis [J].