Exploring the structure-activity relationship of Mincle ligands

Abstract

Mincle is a C-type lectin that plays a critical role in the body’s innate immune response to bacteria and fungi. Compounds identified as ligands for Mincle include trehalose and glycerol esters of complex long chain fatty acids. Harnessing its ability to activate the immune system, trehalose dimycolate has been used as a vaccine adjuvant and for anti-cancer treatment, highlighting the potential use of Mincle immunomodulators in a medical context. To further understand the receptor-ligand interactions and optimise biological activity, the structure-activity relationship of Mincle ligands was investigated through the synthesis and biological evaluation of a series of modified ligands. The preparation of carbohydrate modified trehalose dibehenates was attempted in order to assess the importance of hydroxylprotein interactions, and despite the syntheses being incomplete, improvements on literature methodologies for the regioselective modification of α,α′-D-trehalose were developed. Simplified analogues of the glycerol based natural products identified as Mincle ligands containing straight chain and iso-branched lipids were prepared to evaluate the significance of the branch and establish whether there is a relationship between lipid length and Mincle activation. The corresponding trehalose diester analogues were also synthesised to gauge the capacity of the protein to tolerate changes in the carbohydrate portion of ligands.