Stereochemistry, lipid length and branching influences Mincle agonist activity of monoacylglycerides. Issue 3 (27th November 2019)

• Record Type: Journal Article
• Authors: Khan, Ayesha; Braganza, Chriselle D.; Kodar, Kristel; Timmer, Mattie S. M.; Stocker, Bridget L.
• Is Part Of: Organic & biomolecular chemistry. Volume 18:Issue 3(2019)
• Page Start: 425
• Page End: 430
• Publication Date: 2019-11-27
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c9ob02302j
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Structure activity relationship of Monoacylglycerides shows enhanced Mincle agonist activity of ligands with sn -1 stereochemistry and long-lipid chains through IL-8 production in human peripheral blood monocytes. Abstract : Herein, we report on the synthesis of a series of enantiomerically pure linear, iso-branched, and α-branched monoacyl glycerides (MAGs) in 63–72% overall yield. The ability of the MAGs to signal through human macrophage inducible C-type lectin (hMincle) using NFAT-GFP reporter cells was explored, as was the ability of the compounds to activate human monocytes. From these studies, MAGs with an acyl chain length ≥C22 were required for Mincle activation and the production of interleukin-8 (IL-8) by human monocytes. Moreover, the iso-branched MAGs led to a more pronounced immune response compared to linear MAGs, while an α-branched MAG containing a C-32 acyl chain activated cells to a higher degree than trehalose dibehenate (TDB), the prototypical Mincle agonist. Across the compound classes, the activity of the sn -1 substituted isomers was greater than the sn -3 counterparts. None of the representative compounds were cytotoxic, thus mitigating cytotoxicity as a potential mediator of cellular activity. Taken together, 6h ( sn -1, iC26+1), 8a ( sn -1, C32) and 8b ( sn -3, C32) exhibited the best immunostimulatory properties and thus, have potential as vaccine adjuvants.