Side-chain and backbone amide bond requirements for glycopeptide stimulation of T-cells obtained in a mouse model for rheumatoid arthritis

Holm, Lotta; Bockermann, Robert; Wellner, Erik; Bäcklund, Johan; Holmdahl, Rikard; Kihlberg, Jan

doi:10.1016/j.bmc.2006.05.023

Cited by 12 publications

(23 citation statements)

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“…In addition, the positively correlated regression weight for t2 indicated that hydrogen bond donors/acceptors could be preferred over more lipophilic amino acids. Although the side chain of this residue has been shown to be very important for T-cell stimulations, 25 our model shows that it also influences binding to the A q . By comparison of the relative position in the principal property space of glutamic acid found in rat CII with that of aspartic acid found in mouse CII, it can be seen that glutamic acid is preferred to aspartic acid in position 4.…”

Section: Resultsmentioning

confidence: 85%

“…Similar results were also seen in a recent study reporting significant features for T-cell recognition, where the GalHyl-X-E motif was identified to be extremely important for the T-cell response. 25 The QSAR models of peptides binding the six mouse alleles presented by Hattotuwagama et al did not show a common theme for favored and disfavored amino acid residues. 48 A comparison with the interpretation of our model did not reveal any clear common favored peptide binding pattern between A q and any of the six other modeled mouse MHC class II molecules.…”

Section: Resultsmentioning

confidence: 96%

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Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule A^qAssociated with Autoimmune Arthritis

et al. 2007

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Presentation of (glyco)peptides by the class II major histocompatibility complex molecule Aq to T cells plays a central role in collagen-induced arthritis, an animal model for the autoimmune disease rheumatoid arthritis. A peptide library was designed using statistical molecular design in amino acid space in which five positions in the minimal mouse collagen type II binding epitope CII260-267 were varied. A substantially reduced peptide library of 24 peptides with diverse and representative molecular characteristics was selected, synthesized, and evaluated for the binding strength to Aq. A multivariate QSAR model was established by correlating calculated descriptors, compressed to its principle properties, with the binding data using partial least-square regression. The model was successfully validated by an external test set. Interpretation of the model provided a molecular property binding motif for peptides interacting with Aq. The information may be useful in future research directed toward new treatments of rheumatoid arthritis.

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Section: Resultsmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 96%

Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule A^qAssociated with Autoimmune Arthritis

et al. 2007

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“…It has been shown that the TCRs are sensitive to structural modifications of 1 [8], [10], [13]–[15]. Thus, we adopted a filtering step where we investigated the geometrical similarity of the docking poses of the 11025 peptides and the original peptide pose.…”

Section: Methodsmentioning

confidence: 99%

“…A q [13], [70] and DR4 [7], [8] restricted T-cell hybridomas were used that have been generated previously as reported in the cited literature references. IL-2 production by T-cell hybridomas following incubation with antigen and A q - or DR4-expressing antigen-presenting spleen cells was measured in 96-well flat-bottom microtiter plates essentially as described elsewhere [71], but with slight modifications.…”

Section: Methodsmentioning

confidence: 99%

“…A CII245–270 peptide with the residues Ile 260 , Ala 261 , and Phe 263 exchanged for Ala, hydroxyproline, and Asp, respectively, has been shown to be a competitive inhibitor of antigen-presentation by A q to T cells [12]. Furthermore, structural modifications of 1 with the introduction of different bioisosteres into the glycopeptide backbone typically resulted in strongly reduced A q binding and T-cell responses [13]–[15]. In conclusion, the information gained prior to this study regarding the ternary TCR/pMHC II complexes involving 1 and A q [8]–[10], [12]–[15] shows that the system is sensitive to structural modifications of the (glyco)peptide, in particular the T-cell response which is often diminished.…”

Section: Introductionmentioning

confidence: 99%

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Design of Glycopeptides Used to Investigate Class II MHC Binding and T-Cell Responses Associated with Autoimmune Arthritis

et al. 2011

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The glycopeptide fragment CII259–273 from type II collagen (CII) binds to the murine Aq 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 Aq and DR4 were varied. Synthesis and biological evaluation of the designed glycopeptides provided novel structure-activity relationship (SAR) understanding of binding to Aq 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.

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Modulation of receptor binding to collagen by glycosylated 5‐hydroxylysine: Chemical biology approaches made feasible by Carpino's Fmoc group

Čudić

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The creation of the 9‐fluorenylmethoxycarbonyl (Fmoc) group by the Carpino laboratory facilitated the synthesis of peptides containing acid‐sensitive groups, such as O‐linked glycosides. To fully investigative collagen biochemistry, one needs to assemble peptides that possess glycosylated 5‐hydroxylysine (Hyl). A convenient method for the synthesis of Fmoc‐Hyl(ε‐tert‐butyloxycarbonyl (Boc), O‐tert‐butyldimethylsilyl [TBDMS]) and efficient methods for the synthesis of Fmoc‐Hyl[ε‐Boc,O‐(2,3,4,6‐tetra‐O‐acetyl‐β‐D‐galactopyranosyl)] have been developed. Glycosylated Fmoc‐Hyl derivatives were used to construct a series of types I‐IV collagen‐model triple‐helical peptides (THPs) that incorporated known or proposed receptor binding sites. Glycosylation of Hyl was found to strongly down‐regulate the binding of CD44 and the α3β1 integrin to collagen, while the impact on α2β1 integrin binding was more modest. Molecular modeling of integrin binding indicated that Hyl glycosylation directly impacted the association between the α3β1 integrin metal ion‐dependent adhesion site (MIDAS) and the receptor binding site within type IV collagen. The Fmoc solid‐phase strategy ultimately allowed for chemical biology approaches to be utilized to study tumor cell interactions with glycosylated collagen sequences and document the modulation of receptor interactions by Hyl post‐translational modification.

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Side-chain and backbone amide bond requirements for glycopeptide stimulation of T-cells obtained in a mouse model for rheumatoid arthritis

Cited by 12 publications

References 50 publications

Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule A^qAssociated with Autoimmune Arthritis

Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule A^qAssociated with Autoimmune Arthritis

Design of Glycopeptides Used to Investigate Class II MHC Binding and T-Cell Responses Associated with Autoimmune Arthritis

Modulation of receptor binding to collagen by glycosylated 5‐hydroxylysine: Chemical biology approaches made feasible by Carpino's Fmoc group

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Side-chain and backbone amide bond requirements for glycopeptide stimulation of T-cells obtained in a mouse model for rheumatoid arthritis

Cited by 12 publications

References 50 publications

Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule AqAssociated with Autoimmune Arthritis

Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule AqAssociated with Autoimmune Arthritis

Design of Glycopeptides Used to Investigate Class II MHC Binding and T-Cell Responses Associated with Autoimmune Arthritis

Modulation of receptor binding to collagen by glycosylated 5‐hydroxylysine: Chemical biology approaches made feasible by Carpino's Fmoc group

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Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule A^qAssociated with Autoimmune Arthritis

Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule A^qAssociated with Autoimmune Arthritis