Oxazole-modified glycopeptides that target arthritis-associated class II MHC A(q) and DR4 proteins.
The glycopeptide CII259-273, a fragment from type II collagen (CII), can induce tolerance in mice susceptible to collagen-induced arthritis (CIA), which is a validated disease model for rheumatoid arthritis (RA). Here, we describe the design and synthesis of a small series of modified CII259-273 glycopeptides with oxazole heterocycles replacing three potentially labile peptide bonds. These glycopeptidomimetics were evaluated for binding to murine CIA-associated A(q) and human RA-associated DR4 class II major histocompatibility complex (MHC) proteins. The oxazole modifications drastically reduced or completely abolished binding to A(q). Two of the glycopeptidomimetics were, however, well tolerated in binding to DR4 and they also induced strong responses by one or two DR4-restricted T-cell hybridomas. This work contributes to the development of an altered glycopeptide for inducing immunological tolerance in CIA, with the long-term goal of developing a therapeutic vaccine for treatment of RA.
Andersson
Ida E
IE
Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
Batsalova
Tsvetelina
T
Dzhambazov
Balik
B
Edvinsson
Lotta
L
Holmdahl
Rikard
R
Kihlberg
Jan
J
Linusson
Anna
A
D000577:Amides / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D003094:Collagen / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry; D015195:Drug Design; D006020:Glycopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010080:Oxazoles / Q000737:chemistry*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology
D000577:Amides; D004151:Dipeptides; D006020:Glycopeptides; D000949:Histocompatibility Antigens Class II; D010080:Oxazoles; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D003094:Collagen