Guzelj Samo, Bizjak Špela, Jakopin Žiga
Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, Slovenia.
ACS Med Chem Lett. 2022 Jul 18;13(8):1270-1277. doi: 10.1021/acsmedchemlett.2c00121. eCollection 2022 Aug 11.
The innate immune receptor nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) represents an important target for the development of structurally defined small molecule immunomodulatory compounds that have great potential to be used either as vaccine adjuvants or as general immunostimulatory agents. We report here the investigation of the structure-activity relationship of a series of novel desmuramylpeptide NOD2 agonists. Extensive exploration of chemical space culminated in the discovery of a lipophilic adamantane-moiety-featuring compound , the first single-digit nanomolar and the most potent NOD2 agonist in its structural class to date. Moreover, acted synergistically with lipopolysaccharide and interferon-γ to induce the production of cytokines in human peripheral blood mononuclear cells and enhance their nonspecific cytotoxic activity against K562 cancer cells. These findings provide initial insight into its immunostimulatory potential, especially when used in combination with other immunopotentiators.
天然免疫受体含核苷酸结合寡聚化结构域蛋白2（NOD2）是开发结构明确的小分子免疫调节化合物的重要靶点，这些化合物作为疫苗佐剂或一般免疫刺激剂具有巨大的应用潜力。我们在此报告了一系列新型去muramyl肽NOD2激动剂的构效关系研究。对化学空间的广泛探索最终发现了一种具有亲脂性金刚烷部分的化合物，它是该结构类别中首个纳摩尔级且迄今为止最有效的NOD2激动剂。此外，它与脂多糖和干扰素-γ协同作用，诱导人外周血单个核细胞产生细胞因子，并增强其对K562癌细胞的非特异性细胞毒性活性。这些发现为其免疫刺激潜力提供了初步见解，尤其是在与其他免疫增强剂联合使用时。
