AS: Molecular design, synthesis and mechanism exploration of glycolipid compounds that selectively improve the immune response of Th1.

The team of Du Yuguo and Liu Sijin from the ecological environment research center of Chinese Academy of sciences have found a new class of glycolipid compounds which can selectively enhance Th1 immune response and show strong anti-tumor activity through cross study of computational chemistry, chemical synthesis and molecular immunity. The mechanism study found that they can enhance the binding force of organic molecules to CD1d protein, induce CD1d iNKT axis and CD11b positive Cell activation.key words glycolipid, CD1d, Th1 immune response, antitumor activity, CD11b positive monocytes to explore the immune adjuvant with selective Th1 immune response activation characteristics is of great significance for the treatment of tumor, infection and immune diseases.krn7000 is a kind of α - GalCer type Th1 activator widely recognized and has the potential of drug preparation. Its classical mechanism of action is: it can directly combine with CD1d molecules on the surface of antigen-presenting cells, and then present α - galcer-cd1d complex to TCR receptor of iNKT cells to form CD1d / α - GalCer / TCR ternary complex, and induce the activation of iNKT cells to express a large number of Th1 and Th2 And Th17 inflammatory factors. However, the specificity of α - GalCer for Th1 and Th2 immune response is not strong, which limits its clinical application.studies have found that changing the structure of α - GalCer can significantly affect the expression types of inflammatory factors, but there is no rule that can guide the molecular design of α - GalCer to achieve selective immune regulation of Th1 or Th2.according to the structural characteristics of the binding domain of CD1d / α - GalCer / TCR ternary complex, researchers Du Yuguo and Liu Sijin from the research center of ecological environment, Chinese Academy of Sciences, can enhance the binding capacity of CD1d / α - GalCer / TCR ternary complex under the premise of maintaining the stability of CD1d / α - GalCer / TCR ternary complex by modifying the structure of small organic molecules In addition, it can enhance the anti-tumor activity of Th1.then, based on the chiral template of Glycochemistry, the team members successfully synthesized a multi chiral glycolipid compound α - GalCer diol by introducing a dihydroxy group at the appropriate position in the side chain of glycosyl sheath amine alcohol.further cell and animal experiments confirmed that α - GalCer diol can directly induce the activation of dendritic cells and classic CD1d iNKT axis, and its binding capacity to CD1d receptor is significantly stronger than that of the classical krn7000 compound.at the same time, it was found that α - GalCer diol could increase the number of CD11b positive cells and activate the expression of Th1 type inflammatory factors in mice. Both of them could significantly improve the Th1 type immune response induced by α - GalCer diol, and showed strong anti-tumor metastasis activity in mouse melanoma model test.this study overcomes the disadvantage of non selective induction of anti-inflammatory / pro-inflammatory response factors in the application of α - GalCer. The newly synthesized α - GalCer diol has clinical application potential and has good guiding significance for the development of new anti-tumor drugs.the results were published on advanced science (DOI: org / 10.1002 / advs. 202000609)