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Sökning: WFRF:(Kihlberg Jan) > (2010-2014) > Modified Glycopepti...

Modified Glycopeptides Targeting Rheumatoid Arthritis : Exploring molecular interactions in class II MHC/glycopeptide/T-cell receptor complexes

Andersson, Ida E., 1982- (författare)
Umeå universitet,Kemiska institutionen
Kihlberg, Jan, Professor (preses)
Umeå universitet,Kemiska institutionen
Linusson Jonsson, Anna, Lektor (preses)
Umeå universitet,Kemiska institutionen
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Crews, Craig, Professor (opponent)
Yale University, New Haven, USA
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 (creator_code:org_t)
ISBN 9789174591736
Umeå : Umeå universitet. Kemiska institutionen, 2011
Engelska 65 s.
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)
Abstract Ämnesord
Stäng  
  • 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.

Ämnesord

NATURVETENSKAP  -- Kemi -- Organisk kemi (hsv//swe)
NATURAL SCIENCES  -- Chemical Sciences -- Organic Chemistry (hsv//eng)

Nyckelord

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
Bioorganic chemistry
Bioorganisk kemi
organisk kemi
Organic Chemistry
Biorganic Chemistry
bioorganisk kemi
datorlingvistik
computational linguistics

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