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

Abstract

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.

Immunization with an immunodominant self-peptide derived from glucose-6-phosphate isomerase induces arthritis in DBA/1 mice

“…To identify the immunodominant epitopes we used a set of 15mer peptides overlapping by 11 amino acids that span the whole sequence of human G6PI. Neither G6PI 85–99 nor G6PI 469–483 were predicted by the algorithm used by Iwanami and colleagues [ 30 ], and neither of these two peptides fits the binding motif for I-A q that has been suggested by Holm and colleagues based on their analysis of 24 I-A q -binding peptides [ 37 ] – again supporting the use of unbiased approaches to epitope identification.…”

Structure-Immune Response Relationships of Hapten-Modified Collagen II Peptides in a T-Cell Model of Allergic Contact Dermatitis

“…We made new H-2A q -restricted T-cell hybridomas by fusing B10.QxDBA/1 F1 lymph node cells (LNCs), primed and challenged with CIILysDnp ( 3 ), with the TCR negative variant of thymoma BW 5147. Eleven hybridomas specific to CIILysDnp 3 were identified and cloned several times by limited dilution, until they reached stability, after which they were conserved by freezing, as previously described , . The hybridomas were tested with the synthesized peptides and found to have similar specificities.…”

“…Immunodominant CII sequences used in this and previous , studies, together with the 5- O -(β- d -galactopyranosyl)-5-hydroxy-modified-lysine 264 in the CII 256−270 peptide that has been found to be involved in CIA and RA. The complete Dnp-modified antigen CIILysDnp 3 is also shown.…”

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

“…SMD has been used in ligand-based design of peptides that interact with various protein targets [28]–[30], including MHC proteins [31]. It allows for the identification of amino acid candidates for incorporation into peptides to generate peptide libraries with a balanced range of physicochemical properties, which is important in establishing a reliable SAR.…”