Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China.
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China.
Bioorg Med Chem. 2020 Jan 1;28(1):115141. doi: 10.1016/j.bmc.2019.115141. Epub 2019 Oct 28.
Invariant natural killer T-cells (iNKT-cells) are promising targets for manipulating the immune system, which can rapidly release a large amount of Th1 and Th2 cytokines upon the engagement of their T cell receptor with glycolipid antigens presented by CD1d. In this paper, we wish to report a novel series of α-GalCer analogues which were synthesized by incorporation of l-amino acid methyl esters in the C-6' position of glycolipid. The evaluation of these synthetic analogues for their capacities to stimulate iNKT-cells into producing Th1 and Th2 cytokines both in vitro and in vivo indicated that they were potent CD1d ligands and could stimulate murine spleen cells into a higher release of the Th1 cytokine IFN-γ in vitro. In vivo, Gly-α-GalCer (1) and Lys-α-GalCer (3) showed more Th1-biased responses than α-GalCer, especially analogue 3 showed the highest selectivity for IFN-γ production (IFN-γ/IL-4 = 5.32) compared with α-GalCer (IFN-γ/IL-4 = 2.5) in vivo. These novel α-GalCer analogues might be used as efficient X-ray crystallographic probes to reveal the relationship between glycolipids and CD1d proteins in α-GalCer/CD1d complexes and pave the way for developing new potent immunostimulating agents.
不变自然杀伤 T 细胞 (iNKT 细胞) 是一种有前途的操纵免疫系统的靶点，其 T 细胞受体与 CD1d 呈递的糖脂抗原结合后，能够迅速释放大量 Th1 和 Th2 细胞因子。在本文中，我们希望报告一系列新型的 α-GalCer 类似物，这些类似物是通过在糖脂的 C-6' 位置引入 l-氨基酸甲酯合成的。这些合成类似物对刺激 iNKT 细胞产生 Th1 和 Th2 细胞因子的能力的评估表明，它们是有效的 CD1d 配体，能够刺激小鼠脾细胞在体外产生更高水平的 Th1 细胞因子 IFN-γ。在体内，Gly-α-GalCer (1) 和 Lys-α-GalCer (3) 比 α-GalCer 表现出更强的 Th1 偏向反应，特别是类似物 3 比 α-GalCer (IFN-γ/IL-4 = 2.5) 表现出更高的 IFN-γ 产生选择性（IFN-γ/IL-4 = 5.32）。这些新型的 α-GalCer 类似物可能被用作有效的 X 射线晶体学探针，以揭示 α-GalCer/CD1d 复合物中糖脂与 CD1d 蛋白之间的关系，并为开发新的有效的免疫刺激剂铺平道路。
