ChemMedChem. 2021 Apr 6.
NKT cells play an important role in the immune response and can be activated by glycolipids presented by CD1d protein. We present MCS-0208 an unprecedented arylthioether-phytoceramide able to induce potent iNKT cell activation, notably when tested in human iNKT cells. This arylsphingolipid analog has a simple phenyl group containing a single hydroxyl substituent as a surrogate of the sugar ring. The phenylthioether structure contrasts with a-galactosylceramide (1), the prototypical glycolipid used to induce iNKT cell stimulation, where the galactose 2′-OH and 3′-OH substituents are accepted as the minimal footprint and considered critical for NKT TCR recognition. A computational study supports the recognition of aromatic compound by the CD1d and TCR proteins as radically new structures for NKT cell stimulation.