Department of Chemistry, Seoul National University , Seoul 151-747, Korea.
J Med Chem. 2013 Sep 12;56(17):7100-9. doi: 10.1021/jm400949h. Epub 2013 Aug 26.
We designed and synthesized seven α-GalCer analogues with a pyrazole moiety and varying positions of a phenyl group in the sphingosine backbone to polarize cytokine secretion. On the basis of in vitro and in vivo biological evaluations, we found that analogue 5 induced greater polarization toward Th2 and greater secretion of the immunomodulatory cytokine, IL-4, over secretion of pro-inflammatory cytokines, IFN-γ and IL-17. Treatment of a single dose of analogue 5 markedly ameliorated disease pathogenesis in an animal model of an inflammatory demyelinating disease of the central nervous system, compared to that of KRN7000 (1). Therefore, this new α-GalCer analogue 5 is a novel iNKT ligand that stimulates the selective secretion of anti-inflammatory cytokines and regulates autoimmune diseases by reducing Th1 and Th17 responses.
我们设计并合成了七种带有吡唑基的α-GalCer 类似物，其神经酰胺骨架中苯基团的位置不同，旨在调节细胞因子的分泌。基于体外和体内的生物学评价，我们发现类似物 5 能更有效地诱导 Th2 极化，促进免疫调节细胞因子 IL-4 的分泌，而不是促炎细胞因子 IFN-γ和 IL-17 的分泌。与 KRN7000（1）相比，单次给予类似物 5 治疗可显著改善中枢神经系统炎症性脱髓鞘疾病动物模型的发病机制。因此，这种新型的α-GalCer 类似物 5 是一种新型的 iNKT 配体，它通过减少 Th1 和 Th17 反应来刺激抗炎细胞因子的选择性分泌，并调节自身免疫性疾病。
