title: The glycan role in the glycopeptide immunogenicity revealed by atomistic simulations and spectroscopic experiments on the multiple sclerosis biomarker CSF114(Glc).
abstract: Glycoproteins are often recognized as not-self molecules by antibodies triggering the onset of severe autoimmune diseases such as Multiple Sclerosis (MS). Thus, the development of antigen-mimicking biomarkers represents an attractive strategy for an early diagnosis of the disease. An example is the synthetic glycopeptide CSF114(Glc), which was designed and tested as MS biomarker and whose clinical application was limited by its reduced ability to detect autoantibodies in MS patients. In the attempt to improve the efficacy of CSF114(Glc), we have characterized all the events leading to the final binding of the biomarker to the autoantibody using atomistic simulations, ESR and NMR experiments. The glycosydic moiety plays a primary role in the whole process. In particular, in an environment mimicking that used in the clinical tests the glycopeptide assumes a α-helix structure that is functional for the interaction with the antibody. In this conformation CSF114(Glc) binds the monoclonal antibody mAb8-18C5 similarly to the myelin oligodendrocyte glycoprotein MOG, which is a known MS auto-antigen, thus explaining its diagnostic activity. Our study offers new molecular bases to design more effective biomarkers and provides a most valid protocol to investigate other systems where the environment effect is determinant for the biological activity.
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, I-80131 Naples, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Bruno
authors.affiliation: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Scrima
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, I-80131 Naples, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Napoli "Federico II", Complesso di Monte Sant'Angelo, via Cinthia, 80126 Naples, Italy.
authors.forename: Gerardino
authors.initials: G
authors.lastname: D'Errico
authors.affiliation: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: D'Ursi
authors.affiliation: 1] Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, I-80131 Naples, Italy [2] Università della Svizzera Italiana (USI), Faculty of Informatics, Institute of Computational Science, via G. Buffi 13, CH-6900 Lugano, Switzerland.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites; D015415:Biomarkers; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D006020:Glycopeptides / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology*; D011134:Polysaccharides / Q000737:chemistry* / Q000276:immunology*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D006020:Glycopeptides; D011134:Polysaccharides