Design and Discovery of Covalent α-GalCer Derivatives as Potent CD1d Ligands

Junichiro Kishi, Shinsuke Inuki, Emi Kashiwabara, Takehiro Suzuki, Naoshi Dohmae, Yukari Fujimoto

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)353-359
Number of pages7
JournalACS chemical biology
Volume15
Issue number2
DOIs
Publication statusPublished - 2020 Feb 21

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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