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Synthesis of Asparagine Derivatives Harboring a Lewis X Type DC‐SIGN Ligand and Evaluation of their Impact on Immunomodulation in Multiple Sclerosis
Author(s) -
Doelman Ward,
Marqvorsen Mikkel H. S.,
Chiodo Fabrizio,
Bruijns Sven C. M.,
Marel Gijsbert A.,
Kooyk Yvette,
Kasteren Sander I.,
Araman Can
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202004076
Subject(s) - dc sign , myelin oligodendrocyte glycoprotein , chemistry , glycosylation , glycan , citrullination , ligand (biochemistry) , microbiology and biotechnology , glycoprotein , multiple sclerosis , immune system , dendritic cell , biochemistry , immunology , receptor , biology , experimental autoimmune encephalomyelitis , amino acid , arginine , citrulline
The protein myelin oligodendrocyte glycoprotein (MOG) is a key component of myelin and an autoantigen in the disease multiple sclerosis (MS). Post‐translational N ‐glycosylation of Asn 31 of MOG seems to play a key role in modulating the immune response towards myelin. This is mediated by the interaction of Lewis‐type glycan structures in the N ‐glycan of MOG with the DC‐SIGN receptor on dendritic cells (DCs). Here, we report the synthesis of an unnatural Lewis X (Le X )‐containing Fmoc‐SPPS‐compatible asparagine building block (SPPS=solid‐phase peptide synthesis), as well as asparagine building blocks containing two Le X ‐derived oligosaccharides: LacNAc and Fucα1‐3GlcNAc. These building blocks were used for the glycosylation of the immunodominant portion of MOG (MOG 31‐55 ) and analyzed with respect to their ability to bind to DC‐SIGN in different biological setups, as well as their ability to inhibit the citrullination‐induced aggregation of MOG 31‐55 . Finally, a cytokine secretion assay was carried out on human monocyte‐derived DCs, which showed the ability of the neoglycopeptide decorated with a single Le X to alter the balance of pro‐ and anti‐inflammatory cytokines, inducing a tolerogenic response.