The synthesis and evaluation of chemical adjuvants for modulating immunity

[摘要] Threitol Ceramide (ThrCer) is a truncated, non-glycosidic, acyclic analogue of the prototypical CD1d agonist, α-GalCer, and has potential therapeutic application.Synthesis and biological assessment of a series of deoxy ThrCer analogues showed that all three hydroxyl groups in the sugar head-group are necessary for effective iNKT cell activation.Postulating that the increased conformational flexibility of the acyclic head-group in ThrCer accounts for its lower biological activity compared to α-GalCer, analogues were prepared in which the threitol unit is contained within a carbocycle.Biological results indicate that incorporating the threitol head group into a six- or seven-membered ring can restore activity to similar levels to that displayed by α-GalCer.Routes to double bond-containing carbocyclic analogues have also been explored. In contrast to acquired immunity, innate immunity can act immediately to recruit phagocytes to a site of infection, which can then engulf and disable invading pathogens.Pathogen uptake is usually through pattern recognition receptors, which recognise specific pathogen-associated molecular patterns.Macrophage-inducible C-type lectin (Mincle) is one such receptor which recognises mycobacterial trehalose-6,6’-dimycolate (TDM). Synthesis and biological assessment of TDM analogues revealed that the length of the acyl chain can modulate Mincle stimulation, although the optimal chain length has not yet been determined.

[发布机构] University:University of Birmingham;Department:School of Biosciences

[关键词] Q Science;QD Chemistry