title: Design of glycopeptides used to investigate class II MHC binding and T-cell responses associated with autoimmune arthritis.
abstract: The glycopeptide fragment CII259-273 from type II collagen (CII) binds to the murine A(q) and human DR4 class II Major Histocompatibility Complex (MHC II) proteins, which are associated with development of murine collagen-induced arthritis (CIA) and rheumatoid arthritis (RA), respectively. It has been shown that CII259-273 can be used in therapeutic vaccination of CIA. This glycopeptide also elicits responses from T-cells obtained from RA patients, which indicates that it has an important role in RA as well. We now present a methodology for studies of (glyco)peptide-receptor interactions based on a combination of structure-based virtual screening, ligand-based statistical molecular design and biological evaluations. This methodology included the design of a CII259-273 glycopeptide library in which two anchor positions crucial for binding in pockets of A(q) and DR4 were varied. Synthesis and biological evaluation of the designed glycopeptides provided novel structure-activity relationship (SAR) understanding of binding to A(q) and DR4. Glycopeptides that retained high affinities for these MHC II proteins and induced strong responses in panels of T-cell hybridomas were also identified. An analysis of all the responses revealed groups of glycopeptides with different response patterns that are of high interest for vaccination studies in CIA. Moreover, the SAR understanding obtained in this study provides a platform for the design of second-generation glycopeptides with tuned MHC affinities and T-cell responses.
authors.affiliation: Department of Chemistry, Umeå University, Umeå, Sweden.
authors.forename: Ida E
authors.initials: IE
authors.lastname: Andersson
authors.forename: C David
authors.initials: CD
authors.lastname: Andersson
authors.forename: Tsvetelina
authors.initials: T
authors.lastname: Batsalova
authors.forename: Balik
authors.initials: B
authors.lastname: Dzhambazov
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.forename: Jan
authors.initials: J
authors.lastname: Kihlberg
authors.forename: Anna
authors.initials: A
authors.lastname: Linusson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001667:Binding, Competitive; D019921:Biotinylation; D004353:Drug Evaluation, Preclinical; D006020:Glycopeptides / Q000032:analysis / Q000138:chemical synthesis* / Q000737:chemistry; D015804:HLA-DR4 Antigen / Q000737:chemistry / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006825:Hybridomas; D016018:Least-Squares Analysis; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D025341:Principal Component Analysis; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology*; D014584:User-Computer Interface
chemical_list: D006020:Glycopeptides; D015804:HLA-DR4 Antigen; D000949:Histocompatibility Antigens Class II; D008024:Ligands