The MHC class I-like molecule CD1d is a nonpolymorphic
antigen-presenting
glycoprotein, and its
ligands include
glycolipids, such as α-GalCer. The complexes between CD1d and
ligands activate natural killer T cells by
T cell receptor recognition, leading to the secretion of various
cytokines (IFN-γ, IL-4, IL-17A, etc.). Herein, we report structure-activity relationship studies of α-GalCer derivatives containing various functional groups in their
lipid acyl chains. Several derivatives have been identified as potent CD1d
ligands displaying higher
cytokine induction levels and/or unique
cytokine polarization. The studies also indicated that flexibility of the
lipid moiety can affect the binding affinity, the total
cytokine production level and/or
cytokine biasing. Based on our immunological evaluation and investigation of physicochemical properties, we chose bisamide- and Bz
amide-containing derivatives 2 and 3, and evaluated their in vivo efficacy in a DSS-induced model of
ulcerative colitis. The derivative 3 that exhibits Th2- and Th17-biasing responses, demonstrated significant protective effects against intestinal
inflammation in the DSS-induced model, after a single
intraperitoneal injection.