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4''-O-Alkylated α-galactosylceramide analogues as iNKT-cell antigens : synthetic, biological, and structural studies

  • Janssens, Jonas
  • Bitra, Aruna
  • Wang, Jing
  • Decruy, Tine
  • Venken, Koen
  • Van der Eycken, Johan
  • Elewaut, Dirk
  • Zajonc, Dirk
  • Van Calenbergh, Serge
Publication Date
Jan 01, 2019
Ghent University Institutional Archive
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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, alpha-galactosylceramide (alpha-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 alpha-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 alpha-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 alpha-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 alpha 2-helix of CD1d.

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