Probing Isosteric Replacement for Immunoadjuvant Design: Bis-Aryl Triazole Trehalolipids are Mincle Agonists

Abstract

Herein, we report the modular synthesis and immunological activity of seven bis-aryl triazole trehalolipids (1a–1g) as Brartemicin analogs. The compounds comprised one or two octyloxy (C8) alkyl chains and were synthesized using the venerable CuAAc reaction between the respective aryl acetylenes and a trehalose diazide. A Mincle reporter cell assay revealed that all lipidated analogs activated Mincle. Two compounds, 1c and 1d, produced strong Mincle-dependent immune responses in vitro. The activity was dependent on the degree of alkylation and regiochemistry, with 1c and 1d showing significantly increased IL-1β production in vitro compared to monoalkylated compounds and dialkylated compounds lacking ortho substitution. Molecular docking of 1c positioned the triazole in proximity to Arg-183, which may offer additional interactions that could explain the binding affinity for this class of ligand. These findings demonstrate the capability of triazole-linked Brartemicin analogs as Mincle-mediated Th1/Th17 vaccine adjuvants.