The stimulation of Natural Killer T cells (NKT cells) with alpha-galactosylceramide (aGC) or analogues has been largely studied over the past 20 years, including some clinical trials on disease treatment for humans, singularly in cancer. Despite the evidences of NKT cell implication in immunological responses in a wide range of diseases, and the strong effect of aGC stimulation, the lack of clear improvement of the treatments effects put down the expectations of the use of aGC or derivatives as adjuvants. The research on new analogues with better pharmacological properties has been objective of different groups in the last years looking for different compounds able to reach a more sustainable immune response and a more polarized profile towards Th1 or Th2 type.
Our group is focused on the design and synthesis of aminocyclitol-ceramide derivatives as non-glycosidic aGC analogues, based on our previously described compounds HS44 and HS161.
Different chemical strategies were followed to obtained several sub-families based on our precedent compounds and their biological activity was studied as NKT cells activators. Good immunological profiles were obtained, with interesting Structure-Activity-Relationship (SAR). Some of them showed promising affinity and their crystal structures in complex with mouse CD1d-TCR were obtained. In light of these results, the new aminocyclitol-ceramide derivatives highlight the relevance that small chemical modifications on the antigen polar part have on their biological response.