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Oxazole-modified glycopeptides that target arthritis-associated class II MHC Aq and DR4 proteins
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2010 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 8, no 13, 2931-2940 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
RSC Publishing , 2010. Vol. 8, no 13, 2931-2940 p.
URN: urn:nbn:se:umu:diva-35270DOI: 10.1039/c003640dISI: 000278824700008PubMedID: 20485848OAI: diva2:342867
Available from: 2010-08-11 Created: 2010-08-11 Last updated: 2011-04-08Bibliographically approved
In thesis
1. Modified Glycopeptides Targeting Rheumatoid Arthritis: Exploring molecular interactions in class II MHC/glycopeptide/T-cell receptor complexes
Open this publication in new window or tab >>Modified Glycopeptides Targeting Rheumatoid Arthritis: Exploring molecular interactions in class II MHC/glycopeptide/T-cell receptor complexes
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that leads to degradation of cartilage and bone mainly in peripheral joints. In collagen-induced arthritis (CIA), a mouse model for RA, activation of autoimmune CD4+ T cells depends on a molecular recognition system where T-cell receptors (TCRs) recognize a complex between the class II MHC Aq protein and CII259-273, a glycopeptide epitope from type II collagen (CII). Interestingly, vaccination with the Aq/CII259-273 complex can relieve symptoms and cause disease regression in mice. This thesis describes the use of modified glycopeptides to explore interactions important for binding to the Aq protein and recognition by autoimmune T-cell hybridomas obtained from mice with CIA.

The CII259-273 glycopeptide was modified by replacement of backbone amides with different amide bond isosteres, as well as substitution of two residues that anchor the glycopeptide in prominent pockets in the Aq binding site. A three-dimensional structure of the Aq/glycopeptide complex was modeled to provide a structural basis for interpretation of the modified glycopeptide’s immunological activities. Overall, it was found that the amide bond isosteres affected Aq binding more than could be explained by the static model of the Aq/glycopeptide complex. Molecular dynamics (MD) simulations, however, revealed that the introduced amide bond isosteres substantially altered the hydrogen-bonding network formed between the N-terminal 259-265 backbone sequence of CII259-273 and Aq. These results indicated that the N-terminal hydrogen-bonding interactions follow a cooperative model, where the strength and presence of individual hydrogen bonds depended on the neighboring interactions.

The two important anchor residues Ile260 and Phe263 were investigated using a designed library of CII259-273 based glycopeptides with substitutions by different (non-)natural amino acids at positions 260 and 263. Evaluation of binding to the Aq protein showed that there was scope for improvement in position 263 while Ile was preferred in position 260. The obtained SAR understanding provided a valuable basis for future development of modified glycopeptides with improved Aq binding. Furthermore, the modified glycopeptides elicited varying T-cell responses that generally could be correlated to their ability to bind to Aq. However, in several cases, there was a lack of correlation between Aq binding and T-cell recognition, which indicated that the interactions with the TCRs were determined by other factors, such as presentation of altered epitopes and changes in the kinetics of the TCR’s interaction with the Aq/glycopeptide complex.

Several of the modified glycopeptides were also found to bind well to the human RA-associated DR4 protein and elicit strong responses with T-cell hybridomas obtained from transgenic mice expressing DR4 and the human CD4 co-receptor. This encourages future investigations of modified glycopeptides that can be used to further probe the MHC/glycopeptide/TCR recognition system and that also constitute potential therapeutic vaccines for treatment of RA. As a step towards this goal, three modified glycopeptides presented in this thesis have been identified as candidates for vaccination studies using the CIA mouse model.

Place, publisher, year, edition, pages
Umeå: Umeå universitet. Kemiska institutionen, 2011. 65 p.
Major histocompatibility complex, class II MHC, T-cell receptor, rheumatoid arthritis, collagen-induced arthritis, glycopeptide, amide bond isostere, comparative modeling, rational design, molecular docking, molecular dynamics simulation, statistical molecular design
National Category
Organic Chemistry
Research subject
Organic Chemistry; Biorganic Chemistry; läkemedelskemi
urn:nbn:se:umu:diva-42082 (URN)978-91-7459-173-6 (ISBN)
Public defence
2011-04-29, KBC-huset, KB3B1, Umeå Universitet, Umeå, 10:00 (English)
Available from: 2011-04-08 Created: 2011-04-05 Last updated: 2011-04-11Bibliographically approved

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Andersson, Ida E.Edvinsson, LottaKihlberg, JanLinusson, Anna
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