In the neurodegenerative autoimmune disease multiple sclerosis (MS) the protein myelin oligodendrocyte glycoprotein (MOG) has been identified as the key autoantigen behind the demyelinating pathology1. Previous work from our group shows that decoration of this protein with an N-glycan containing fucosylated Lewis-type sugars, known ligands for the Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN) receptor, plays an important role in immunotolerance towards MOG2. However, this work was performed on myelin as a whole and included heterogeneous mixtures of N-glycans. Furthermore, we recently showed that these peptides have amyloid-like aggregation behavior when citrillunated3 and are interested in the effect of glycosylation on this aggregation.
To investigate the role of fucosylated sugars on MOG antigenicity, we decided to extent the commonly used antigenic peptide of MOG (MOG35-55) on the N-terminus to include the natural N-glycosylation site (Asn31). Using novel chemistry developed in our lab, we have synthesized Fmoc-asparagine building block decorated with various protected glycans, including a derivative of the known DC-SIGN ligand Lewis X. In my talk, I will present the synthesis of these glycosylated asparagine building blocks and their application in the solid phase peptide synthesis (SPPS) of homogeneously glycosylated MOG peptides. Furthermore, I will show the results of the aggregation assays of the glycosylated peptides as well as the results of our first biological assays showing that the Lewis X modified MOG peptides are capable of binding to DC-SIGN in vitro.
- Jagessar et al. (2008) J. Neuropathol. Exp. Neurol. 67 (4), 326−40.
- García-Vallejo et al. (2014) J. Exp. Med. 211 (7), 1465-1483
- Araman et al. (2019) Biochemistry, 58 (6). 763–775