Lipidated Brartemicin Analogues Are Potent Th1-Stimulating Vaccine Adjuvants

Effective
Th1-stimulating vaccine adjuvants typically activate antigen presenting
cells (APCs) through pattern recognition receptors (PRRs). Macrophage
inducible C-type lectin (Mincle) is a PRR expressed on APCs and has
been identified as a target for Th1-stimulating adjuvants. Herein,
we report on the synthesis and adjuvanticity of rationally designed
brartemicin analogues containing long-chain lipids and demonstrate
that they are potent Mincle agonists that activate APCs to produce
inflammatory cytokines in a Mincle-dependent fashion. Mincle binding,
however, does not directly correlate to a functional immune response.
Mutation studies indicated that the aromatic residue of lead compound 9a has an important interaction with Mincle Arg183. In vivo assessment of 9a highlighted the capability of this
analogue to augment the Th1 response to a model vaccine antigen. Taken
together, our results show that lipophilic brartemicin analogues are
potent Mincle agonists and that 9a has superior in vivo
adjuvant activity compared to TDB.