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Issue 7, 2011
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Synthesis of serine-based glycolipids as potential TLR4 activators

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Abstract

A new series of monosaccharide-based glycolipids devoid of phosphate groups and with two lipid chains were rationally designed by varying the lipid chain lengths and saccharide structure of a α-GalCer-derived lead compound (CCL-34) that is a potent TLR4 agonist. The NF-κB activity of a 60-membered galactosyl serine-based synthetic library containing compounds with various lipid chain lengths was measured in a HEK293 cell line that stably expressed human TLR4, MD2, and CD14 (293-hTLR4/MD2-CD14). The results showed that the optimal carbon chain lengths for the lipid amine and fatty acid to activate TLR4 were 10–11 and 12, respectively. Evaluation of a 20-membered synthetic glycosyl serine-based lipid library containing compounds with various saccharide moieties and fixed lipid chain lengths revealed that the galactose moiety in CCL-34 could be replaced by glucose without loss of activity (CCL-34-S3 and CCL-34-S16). Changing the orientation of the anomeric glycosidic bond of CCL-34 resulted in a complete loss of activity (β-CCL34). Surprisingly, a change in configuration of the anomeric glycosidic bond in a glucosyl glycolipid is tolerable (CCL-34-S14). Another noteworthy observation is that the activity of a L-fucosyl derived glycolipid (CCL-34-S13) was comparable to that of CCL-34. In sum, this study determines the structural features that are crucial for an optimal TLR4-stimulating activity. It also provides several molecules with immunostimulating potential.

Graphical abstract: Synthesis of serine-based glycolipids as potential TLR4 activators

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Publication details

The article was received on 06 Nov 2010, accepted on 22 Dec 2010 and first published on 21 Feb 2011


Article type: Paper
DOI: 10.1039/C0OB00990C
Citation: Org. Biomol. Chem., 2011,9, 2492-2504
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    Synthesis of serine-based glycolipids as potential TLR4 activators

    L. Huang, H. Lin, P. Huang, W. Hsiao, L. V. Raghava Reddy, S. Fu and C. Lin, Org. Biomol. Chem., 2011, 9, 2492
    DOI: 10.1039/C0OB00990C

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