4“‐O‐Alkylated α‐Galactosylceramide Analogues as iNKT‐Cell Antigens: Synthetic, Biological, and Structural Studies

• Published in: ChemMedChem 2019-01, Vol.14 (1), p.147-168
• Main Authors: Janssens, Jonas, Bitra, Aruna, Wang, Jing, Decruy, Tine, Venken, Koen, van der Eycken, Johan, Elewaut, Dirk, Zajonc, Dirk M., van Calenbergh, Serge
• Format: Article
• Language: English
• Subjects: Alkylation; Animals; Antigens; Antigens - chemistry; Antigens - immunology; CD1d antigen; Crystal structure; Cytokines; Dose-Response Relationship, Drug; Galactosylceramide; Galactosylceramides - chemical synthesis; Galactosylceramides - chemistry; Galactosylceramides - immunology; glycolipid antigens; Glycolipids; Humans; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Immune response; Immune system; Immunogenicity; Inflammation; iNKT-cell activation; KRN7000; Lymphocytes; Lymphocytes T; Mice; Molecular Structure; Natural killer cells; Natural Killer T-Cells - immunology; Natural products; Organic chemistry; Structure-Activity Relationship; α-galactosylceramide; α-GalCer analogues
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201800649

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. Pro‐inflammatory cytokine polarization: Introducing (aryl)alkyl groups at the 4“‐position of the semi‐synthetic glycolipid α‐GalCer retains immunostimulating capacity in mice. Introduction of benzyl‐type modifications induces a pro‐inflammatory cytokine profile, which may eventually lead to therapeutically useful compounds for the treatment of cancer and autoimmune diseases, or as vaccine adjuvants.