Premium
4“‐O‐Alkylated α‐Galactosylceramide Analogues as i NKT‐Cell Antigens: Synthetic, Biological, and Structural Studies
Author(s) -
Janssens Jonas,
Bitra Aruna,
Wang Jing,
Decruy Tine,
Venken Koen,
van der Eycken Johan,
Elewaut Dirk,
Zajonc Dirk M.,
van Calenbergh Serge
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800649
Subject(s) - glycolipid , cd1d , natural killer t cell , moiety , immune system , antigen , stereochemistry , chemistry , alkylation , t cell , biology , biochemistry , immunology , catalysis
Invariant natural killer T‐cells ( i NKT) 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 i NKT‐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.