Structure-activity relationship (SAR) in monosaccharide-based Toll-like receptor 4 (TLR4) antagonists

Facchini, Fabio A and Zaffaroni, Lenny and Minotti, Alberto and Rapisarda, Silvia and Calabrese, Valentina and Forcella, Matilde and Fusi, Paola and Airoldi, Cristina and Ciaramelli, Carlotta and Billod, Jean-Marc and Schromm, Andra and Braun, Harald and Palmer, Charys and Beyaert, Rudi and Jerala, Roman and Pirianov, Grisha and Martin-Santamaria, Sonsoles and Peri, Francesco (2018) Structure-activity relationship (SAR) in monosaccharide-based Toll-like receptor 4 (TLR4) antagonists. Journal of Medicinal Chemistry, 61 (7). pp. 2895-2909. ISSN 1520-4804

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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 to 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. FT-IR, NMR, and SAXS measurements suggested that the aggregation state in aqueous solution depends on fatty acid chains lengths and that this property can influence TLR4 activity in this series of compounds.

Item Type: Journal Article
Keywords: Toll like receptor 4, Toll like receptor 4 antagonists
Faculty: ARCHIVED Faculty of Science & Technology (until September 2018)
Depositing User: Grisha Pirianov
Date Deposited: 12 Apr 2018 10:58
Last Modified: 09 Sep 2021 18:57

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