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Stereochemistry, lipid length and branching influences Mincle agonist activity of monoacylglycerides

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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.

Graphical abstract: Stereochemistry, lipid length and branching influences Mincle agonist activity of monoacylglycerides

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Publication details

The article was received on 24 Oct 2019, accepted on 19 Nov 2019 and first published on 20 Nov 2019


Article type: Paper
DOI: 10.1039/C9OB02302J
Org. Biomol. Chem., 2020, Advance Article

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    Stereochemistry, lipid length and branching influences Mincle agonist activity of monoacylglycerides

    A. Khan, C. D. Braganza, K. Kodar, M. S. M. Timmer and B. L. Stocker, Org. Biomol. Chem., 2020, Advance Article , DOI: 10.1039/C9OB02302J

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