Th1-stimulating vaccine adjuvants often target the innate immune system through the activation of antigen presenting cells (APCs). APCs can recognise molecules through pattern recognitions receptors (PRRs) such as the Macrophage inducible C-type lectin (Mincle), which has been identified as an attractive target for the generation of Th1-stimulating adjuvants. Brartemicin, a natural product incorporating the glucose dimer trehalose, was noted to share strucural features with the gold-standard Mincle agonist, trehalose dibehenate. In this work, a range of Brartemicin analogues incorporating long-chain lipids were prepared and assessed for their ability to signal through Mincle and induce a Th1-polarised immune response. Using a range of <i>in vitro</i> assays, we demonstrated that Brartemicin analogues containing long-chain lipids are potent Mincle agonists and can activate APCs to produce an inflammatory response in a Mincle-dependent manner. Furthermore, employment of mutation studies indicated that a model lipidated-Brartemicin analogue had important interactions with Mincle Arg183. Analysis of a representative ligand in an <i>in vivo</i> model highlighted the ability of lipidated-Brartemicin derivatives to augment the Th1-response to a model vaccine antigen and the response induced by the lipidated-Brartemicin derivative was found to be superior to that of the current gold-standard Mincle agonist, trehalose dibehenate.

Trehalose glycolipid derived vaccine adjuvants: Lipidated Brartemicin analogues are potent Mincle agonists

ACS Spring Meeting 2021

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