Structure-activity relationship studies of Bz amide-containing α-GalCer derivatives as natural killer T cell modulators

Junichiro Kishi, Shinsuke Inuki, Natsumi Hirata, Emi Kashiwabara, Daisuke Yoshidome, Osamu Ichihara, Yukari Fujimoto

Research output: Contribution to journalArticle

Abstract

CD1d is a non-polymorphic antigen-presenting glycoprotein that recognizes glycolipids as ligands. Ligands bind to the hydrophobic grooves of CD1d, and the resulting ligand-CD1d complexes activate natural killer T (NKT) cells by means of T cell receptor recognition, leading to the secretion of various cytokines. However, details of the ligand recognition mechanism of a large hydrophobic ligand binding pocket and the relationship between cytokine induction and ligand structure are unclear. We report the synthesis of α-GalCer derivatives containing a Bz amide group having various substituting groups in the ceramide moiety, and the analysis of the structure-activity relationships. The assays reveal that the Bz amide-containing CD1d ligands function as NKT cell modulators displaying Th2 cytokine biasing responses. Furthermore, molecular dynamics simulation studies suggest that the phenyl groups can interact with the aromatic amino acid residues in the lipid binding pocket of CD1d.

Original languageEnglish
Pages (from-to)970-973
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number8
DOIs
Publication statusPublished - 2019 Apr 15

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Natural Killer T-Cells
T-cells
Structure-Activity Relationship
Amides
Modulators
Ligands
Derivatives
Cytokines
Aromatic Amino Acids
Ceramides
Glycolipids
Molecular Dynamics Simulation
T-Cell Antigen Receptor
Molecular dynamics
Assays
Glycoproteins
Lipids
Antigens
Computer simulation

Keywords

  • CD1d
  • Glycolipid
  • Structure-activity relationships
  • α-GalCer

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Structure-activity relationship studies of Bz amide-containing α-GalCer derivatives as natural killer T cell modulators. / Kishi, Junichiro; Inuki, Shinsuke; Hirata, Natsumi; Kashiwabara, Emi; Yoshidome, Daisuke; Ichihara, Osamu; Fujimoto, Yukari.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 8, 15.04.2019, p. 970-973.

Research output: Contribution to journalArticle

Kishi, Junichiro ; Inuki, Shinsuke ; Hirata, Natsumi ; Kashiwabara, Emi ; Yoshidome, Daisuke ; Ichihara, Osamu ; Fujimoto, Yukari. / Structure-activity relationship studies of Bz amide-containing α-GalCer derivatives as natural killer T cell modulators. In: Bioorganic and Medicinal Chemistry Letters. 2019 ; Vol. 29, No. 8. pp. 970-973.
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AU - Kashiwabara, Emi

AU - Yoshidome, Daisuke

AU - Ichihara, Osamu

AU - Fujimoto, Yukari

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