The bacterial peptidoglycan (PGN) constituent muramyl dipeptide (MDP) and its congeners possess immuno-adjuvant activity, and find applications in vaccines to potentiate the immune response of antigens. It confers non-specific resistance towards pathogenic infections and defense against tumors. In this work, the parent MDP molecule is re-designed by replacing its carbohydrate moiety with an immunoregulatory xanthine scaffold, while conserving the l-d configuration of the pharmacophore. Alkyl chains are introduced at the C-terminus of d-isoglutamine to help the molecules access cytoplasmic NOD2 receptors and activate the innate immune system. Lipophilic MDP congeners are thus obtained by adopting a direct or indirect convergent synthetic route with overall yields of >50%. We found that an indirect approach can reliably be implemented on gram scale, thereby unlocking access to substantial amounts of pathogen-associated molecular patterns for in vivo studies, which will accelerate the development of NOD2 immuno-adjuvants against viral and bacterial infections.

细菌肽聚糖 (PGN) 的组成成分胞壁酰二肽 (MDP) 及其同类物具有免疫佐剂活性，并在疫苗中得到应用以增强抗原的免疫反应。它赋予对病原体感染的非特异性抵抗力和对肿瘤的防御能力。在这项工作中，通过用免疫调节黄嘌呤支架替换其碳水化合物部分来重新设计母体 MDP 分子，同时保留升-d药效团的配置。烷基链在C端引入d-异谷氨酰胺帮助分子进入细胞质 NOD2 受体并激活先天免疫系统。因此，通过采用直接或间接收敛合成路线获得亲脂性 MDP 同系物，总收率 > 50%。我们发现间接方法可以在克尺度上可靠地实施，从而为体内研究打开大量病原体相关分子模式的通道，这将加速针对病毒和细菌感染的 NOD2 免疫佐剂的开发。