Th2-biasing CD1d ligands are attractive potential candidates for adjuvants and therapeutic drugs. However, the number of potent ligands is limited, and their biasing mechanism remain unclear. Herein, a series of novel Th2-biasing CD1d glycolipid ligands, based on modification of their lipid part, have been identified. These have shown high binding affinities and efficient Th2 cytokine production. Importantly, the truncated acyl chain containing variants still retain their binding affinities and agonistic activities, which can be associated with an "anchoring effect," that is, formation of a buried hydrogen bond between a polar group on the acyl chain and the CD1d lipid-binding pocket. The analysis indicated that the appearance rates of ligand-CD1d complexes on the cell surface were involved in Th2-biasing responses. The designed ligands, having the anchor in the shorter lipid part, are one of the most potent Th2-biasing ligands among the known ligands.

Indoleamine 2,3-dioxygenase 1 (IDO1) has emerged as a key target for cancer therapy, as IDO1 plays a critical role in the capacity of tumor cells to evade the immune system. The pyrrolopiperazinone alkaloid longamide B and its derivatives were identified as novel IDO1 inhibitors based on docking studies and small library synthesis. The thioamide derivative showed higher IDO1 inhibitory activity than longamide B, and displayed an activity similar to that of a representative IDO1 inhibitor, 1-methyl-tryptophan. These results suggest that the pyrrolopiperazinone scaffold of longamide B could be used in the development of IDO1 inhibitors.

No abstract

CD1d is a nonpolymorphic antigen-presenting protein responsible for the regulation of natural killer T (NKT) cell activation. α-Galactosyl ceramide (α-GalCer, KRN7000) is the representative CD1d ligand that can bind to the CD1d protein. The resulting complex is recognized by the T cell receptors of the NKT cell, inducing various immune responses. Previous structure–activity relationship studies of α-GalCer have revealed that the ability of NKT cells to induce cytokines depends on the ligand structure, and in particular, ligands that form more stable complexes with CD1d display potent activity. We focused on the Cys residue of the large hydrophobic pockets of CD1d (A′ pocket) and developed α-GalCer derivatives containing groups that can form covalent bonds. The assay results revealed that these ligands displayed higher levels of cytokine production and Th2 cell-type cytokine polarization response. Furthermore, the LC-MS/MS analysis indicated that the chloroacetylamide-containing ligand was covalently bound to Cys12 of CD1d, which suggests that the enhanced activities result from the formation of a stable CD1d–ligand complex. To our knowledge, this is the first ligand that allows covalent bond formation to CD1d under physiological conditions.

Th2-biasing CD1d ligands are attractive potential candidates for adjuvants and therapeutic drugs.H owever,t he number of potent ligands is limited, and their biasing mechanism remain unclear.H erein, as eries of novel Th2biasing CD1d glycolipid ligands,b ased on modification of their lipid part, have been identified. These have shown high binding affinities and efficient Th2 cytokine production. Importantly,t he truncated acyl chain containing variants still retain their binding affinities and agonistic activities,whichcan be associated with an "anchoring effect,"t hat is,f ormation of ab uried hydrogen bond between ap olar group on the acyl chain and the CD1d lipid-binding pocket. The analysis indicated that the appearance rates of ligand-CD1d complexes on the cell surface were involved in Th2-biasing responses.The designed ligands,having the anchor in the shorter lipid part, are one of the most potent Th2-biasing ligands among the known ligands.