Semi-synthetic strategy to obtain aberrantly N31-glucosylated Myelin Oligodendrocyte Glycoprotein

Inflammatory, demyelinating diseases of the central nervous system (CNS) comprise a broad spectrum of mechanistically heterogeneous disorders of which multiple sclerosis (MS) is the most common [1]. There is strong evidence that antibody (Ab) dependent mechanisms contribute to the pathogenesis in at least a subset of patients with CNS inflammation [2]. Even if its role as putative autoantigen in MS and in its animal models is still matter of debate, Myelin Oligodendrocyte Glycoprotein (MOG) is one of the best studied candidate autoantigen. This hypothesis arises from its localization on the outermost surface of myelin sheaths, enabling the access of auto-Abs to MOG extracellular domain. Numerous studies are based on MOG and anti-MOG Ab detection using different protein preparations and protocols. This is the reason of inhomogeneous and controversial data on the role of MOG in MS autoimmune response. In this context, we reported the use of properly folded extracellular domain of ratMOG(1-117), produced in E.coli, demonstrating that anti-MOG Abs are not relevant in a statistically significant number of MS patients [3]. Conversely, we reported that the structure-based designed N-glucosylated type I’ beta-turn peptide, CSF114(Glc) is able to detect specific and high affinity Abs in MS patients. Therefore, we proposed that CSF114(Glc) is a mimic of aberrantly post-translationally modified myelin antigens [4,5]. Based on these findings, we hypothesize that aberrant N-glucosylation of Asn31, native glycosylation site of hMOG, is involved in the etiopathogenesis of MS. We decided to develop a semisynthetic strategy to produce N-glucosylated hMOG by Native Chemical Ligation (NCL).