4"-O-Alkylated α-Galactosylceramide Analogues As INKT-Cell Antigens: Synthetic, Biological, and Structural Studies

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2018 Dec 18

PMID 30556652

Citations 7

Authors

Jonas Janssens

Aruna Bitra

Jing Wang

Tine Decruy

Koen Venken

Johan Van der Eycken

Dirk Elewaut

Dirk M Zajonc

Serge Van Calenbergh

Affiliations

Soon will be listed here.

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.

Citing Articles

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