title: Synthesis of serine-based glycolipids as potential TLR4 activators.
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.
authors.affiliation: Department of Chemistry, National Tsing Hua University, 101 Sec. 2, Kuang Fu Rd, Hsinchu 30013, Taiwan.
authors.forename: Li-De
authors.initials: LD
authors.lastname: Huang
authors.forename: Hong-Jyune
authors.initials: HJ
authors.lastname: Lin
authors.forename: Po-Hsiung
authors.initials: PH
authors.lastname: Huang
authors.forename: Wei-Chen
authors.initials: WC
authors.lastname: Hsiao
authors.forename: L Vijaya Raghava
authors.initials: LV
authors.lastname: Reddy
authors.forename: Shu-Ling
authors.initials: SL
authors.lastname: Fu
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Lin
mesh_terms: D002460:Cell Line; D006017:Glycolipids / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000819:agonists*
chemical_list: D006017:Glycolipids; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D012694:Serine