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4"-O-Alkylated α-Galactosylceramide Analogues as iNKT-Cell Antigens: Synthetic, Biological, and Structural Studies.

Authors
  • Janssens, Jonas1, 2
  • Bitra, Aruna3
  • Wang, Jing3
  • Decruy, Tine4, 5
  • Venken, Koen4, 5
  • van der Eycken, Johan2
  • Elewaut, Dirk4, 5
  • Zajonc, Dirk M3, 4
  • van Calenbergh, Serge1
  • 1 Laboratory for Medicinal Chemistry, Department of Pharmaceutics (FFW), Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium. , (Belgium)
  • 2 Laboratory for Organic and Bioorganic Synthesis, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 (S4), 9000, Ghent, Belgium. , (Belgium)
  • 3 Division of Immune Regulation, La Jolla Institute for Allergy and Immunology (LJI), 9420 Athena Circle, La Jolla, CA, 92037, USA.
  • 4 Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium. , (Belgium)
  • 5 VIB Inflammation Research Center, UGent-VIB Research Building FSVM, Technologiepark 927, 9052, Zwijnaarde (Ghent), Belgium. , (Belgium)
Type
Published Article
Journal
ChemMedChem
Publisher
Wiley (John Wiley & Sons)
Publication Date
Jan 08, 2019
Volume
14
Issue
1
Pages
147–168
Identifiers
DOI: 10.1002/cmdc.201800649
PMID: 30556652
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Invariant natural killer T-cells (iNKT) are a glycolipid-responsive subset of T-lymphocytes that fulfill a pivotal role in the immune system. The archetypical synthetic glycolipid, α-galactosylceramide (α-GalCer), whose molecular framework is inspired by a group of amphiphilic natural products, remains the most studied antigen for iNKT-cells. Nonetheless, the potential of α-GalCer as an immunostimulating agent is compromised by the fact that this glycolipid elicits simultaneous secretion of Th1- and Th2-cytokines. This has incited medicinal chemistry efforts to identify analogues that are able to perturb the Th1/Th2 balance. In this work, we present the synthesis of an extensive set of 4"-O-alkylated α-GalCer analogues, which were evaluated in vivo for their cytokine induction. We have found that conversion of the 4"-OH group to ether moieties decreases the immunogenic potential in mice relative to α-GalCer. Yet, the benzyl-modified glycolipids are able to produce a distinct pro-inflammatory immune response. The crystal structures suggest an extra hydrophobic interaction between the benzyl moiety and the α2-helix of CD1d. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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