Pirianov_2018.docx (4.26 MB)
Structure-activity relationship (SAR) in monosaccharide-based Toll-like receptor 4 (TLR4) antagonists
journal contribution
posted on 2023-08-30, 15:14 authored by Fabio A Facchini, Lenny Zaffaroni, Alberto Minotti, Silvia Rapisarda, Valentina Calabrese, Matilde Forcella, Paola Fusi, Cristina Airoldi, Carlotta Ciaramelli, Jean-Marc Billod, Andra Schromm, Harald Braun, Charys Palmer, Rudi Beyaert, Roman Jerala, Grisha Pirianov, Sonsoles Martin-Santamaria, Francesco PeriThe 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.
History
Refereed
- Yes
Volume
61Issue number
7Page range
2895-2909Publication title
Journal of Medicinal ChemistryISSN
1520-4804External DOI
Publisher
American Chemical SocietyFile version
- Accepted version
Language
- eng
Official URL
Legacy posted date
2018-04-12Legacy creation date
2018-04-12Legacy Faculty/School/Department
ARCHIVED Faculty of Science & Technology (until September 2018)Usage metrics
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