1 research outputs found
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 <b>9a</b> has an important interaction with Mincle Arg183. In vivo assessment of <b>9a</b> 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 <b>9a</b> has superior in vivo
adjuvant activity compared to TDB