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.

中文翻译：

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脂质溴化青霉素类似物是有效的Th1刺激疫苗佐剂。

有效的刺激Th1的疫苗佐剂通常通过模式识别受体（PRR）激活抗原呈递细胞（APC）。巨噬细胞诱导型C型凝集素（Mincle）是在APC上表达的PRR，已被确定为刺激Th1的佐剂的靶标。在本文中，我们报告了合理设计的含有长链脂质的Braartemicin类似物的合成和佐剂作用，并证明它们是有效的Mincle激动剂，可激活Mining-dependent方式产生APC的炎性细胞因子。然而，微粒结合不与功能性免疫应答直接相关。突变研究表明，铅化合物9a的芳族残基与Mincle Arg183具有重要的相互作用。9a的体内评估强调了该类似物增强对模型疫苗抗原的Th1反应的能力。两者合计，我们的研究结果表明，亲脂性的brartemicin类似物是有效的Mincle激动剂，与TDB相比，9a具有更好的体内佐剂活性。