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

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.