There is a need for improved vaccine adjuvants to augment vaccine efficacy. One way to address this is by targeting multiple immune cell pathogen recognition receptors (PRRs) using chimeric pathogen-associated molecular patterns (PAMPs). Conjugation of the PAMPs will ensure codelivery of the immunostimulatory molecules to the same cell, enhancing adjuvant activity. The macrophage inducible C-type lectin (Mincle) is a promising PRR for adjuvant development; however, no effective chimeric Mincle adjuvants have been prepared. We addressed this by synthesizing Mincle adjuvant conjugates, MDP-C18Brar and MDP-C18Brar-dilipid, which contain PAMPs recognized by Mincle and the nucleotide-binding oligomerization domain 2 (NOD2). The two PAMPs are joined by a pH-sensitive oxyamine linker which, upon acidification at lysosomal pH, hydrolyzed to release the NOD2 ligands. The conjugates elicited the production of Th1 and Th17 promoting cytokines in vitro, and when using OVA as a model antigen, exhibited enhanced T-cell-mediated immune responses and reduced toxicity in vivo, compared to the coadministration of the adjuvants.

中文翻译：

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作为疫苗佐剂的嵌合 NOD2 Mincle 激动剂

需要改进的疫苗佐剂以增强疫苗功效。解决这个问题的一种方法是使用嵌合病原体相关分子模式 (PAMP) 靶向多个免疫细胞病原体识别受体 (PRR)。 PAMP 的缀合将确保免疫刺激分子同时递送至同一细胞，从而增强佐剂活性。巨噬细胞诱导型 C 型凝集素 (Mincle) 是一种很有前景的 PRR，可用于佐剂开发；然而，尚未制备出有效的嵌合Mincle佐剂。我们通过合成 Mincle 佐剂缀合物 MDP-C18Brar 和 MDP-C18Brar-dilipid 解决了这个问题，它们含有 Mincle 识别的 PAMP 和核苷酸结合寡聚结构域 2 (NOD2)。两个 PAMP 通过 pH 敏感的氧胺连接体连接，在溶酶体 pH 值酸化时，该连接体水解释放 NOD2 配体。该缀合物在体外引发 Th1 和 Th17 促进细胞因子的产生，并且当使用 OVA 作为模型抗原时，与佐剂的共同给药相比，在体内表现出增强的 T 细胞介导的免疫反应和降低的毒性。