Synthesis and computational studies of Bacteroides Fragilis lipid a analogues

Lipid A is a glycolipid which is the active principle of lipopolysaccharide well known to stimulate innate immune system through recognition by the Toll-Like receptor 4. Although canonical E. coli lipid A is too toxic and hence limited for vaccine adjuvant utilization, low toxic lipid A derivatives such as monophosphoryl lipid A (MPL)1 have been produced through structural modification. In particular, 3D-MPL2 which is an MPL analogue, was approved as a safe adjuvant for use in human papillomavirus vaccine and hepatitis B vaccine. On the other hand, symbiotic bacteria Lipid As are recently attracting attention for development of novel safe adjuvants. In 2019, the group of Kasper discovered monophopshorylated glycolipids covalently attached to immunomodulatory capsular polysaccharide A (PSA) of symbiotic Bacteroides fragilis, and found out that these lipids, which have a similar structure to Lipid A, are critical to the immunomodulatory activity and therapeutic potential of PSA3. However, the exact structure of the glycolipids is not well known and structure-activity relationship is not clear. Therefore, as collaborative work with Kasper’s group, in the present communication we report on the synthesis of a library of predicted B. fragilis PSA-attached lipid A analogues for investigation of structure-activity relationship. In addition, preliminary computational studies were performed to explore the possible binding modes of the designed ligands within the target receptor.