title: Cyclodimerization of immunosuppressive fragment of HLA-DR molecule. Design, synthesis and ESI-MS/MS analysis.
abstract: The nonapeptide fragment of the HLA-DR molecule, located in the exposed loop of the alpha-chain (164-172), having the VPRSGEVYT sequence, suppresses the immune response. Based on the three-dimensional structure of the HLA-DR superdimer, we designed a new cyclodimeric analog in which the two parallel peptide chains of VPRSGEVYT sequence are linked through their C-termini by spacer of (Gly5 )2 -Lys-NH2 and the N-termini are also linked by poly(ethylene glycol). The (VPRSGEVYTG5 )2 K-resin analog was synthesized using solid-phase peptide synthesis protocols. The cyclization was achieved by cross-linking the N-terminal positions of the dimeric peptide, attached to a MBHA resin, with alpha, omega-bis (acetic acid) poly(ethylene glycol), activated by esterification with pentafluorophenol. Our results demonstrate that the cyclodimerization of VPRSGEVYT results in enhanced immunosuppressive activity of the peptide. Mass spectrometry fragmentation analysis of the obtained cyclodimeric peptide is also presented. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.
authors.affiliation: Faculty of Chemistry, University of Wroclaw, Wroclaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Biernat
authors.affiliation: Faculty of Chemistry, University of Wroclaw, Wroclaw, Poland.|Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Marzena
authors.initials: M
authors.lastname: Cydzik
authors.affiliation: Faculty of Chemistry, University of Wroclaw, Wroclaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Stefanowicz
authors.affiliation: Faculty of Chemistry, University of Wroclaw, Wroclaw, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Kluczyk
authors.affiliation: Institute of Immunology and Experimental Therapy, PAS, Wrocław, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Artym
authors.affiliation: Institute of Immunology and Experimental Therapy, PAS, Wrocław, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Zimecki
authors.affiliation: Faculty of Chemistry, University of Wroclaw, Wroclaw, Poland.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Szewczuk
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000187:drug effects*; D003432:Cross-Linking Reagents / Q000737:chemistry; D003500:Cyclization; D019281:Dimerization; D015195:Drug Design; D004912:Erythrocytes / Q000166:cytology / Q000276:immunology; D005464:Fluorobenzenes / Q000737:chemistry; D006684:HLA-DR Antigens / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000494:pharmacology; D010636:Phenols / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D061251:Primary Cell Culture; D017433:Protein Structure, Secondary; D012756:Sheep; D060327:Solid-Phase Synthesis Techniques; D021241:Spectrometry, Mass, Electrospray Ionization; D005466:Fluorocarbons
chemical_list: D000906:Antibodies; D003432:Cross-Linking Reagents; D005464:Fluorobenzenes; D006684:HLA-DR Antigens; D007166:Immunosuppressive Agents; D010446:Peptide Fragments; D010636:Phenols; D011092:Polyethylene Glycols; C085539:2,3,4,5,6-pentafluorophenol; D005466:Fluorocarbons
keywords: ESI-MSMS; HLA-DR analogs; PEG linker; cyclodimer