Design of gliadin peptide analogues with low affinity for the celiac disease associated HLA-DQ2 protein.
The HLA-DQ2.5 receptors bind gluten-derived peptides and present them to the T cells in the intestinal mucosa thus inducing the development of immune responses typical of the celiac disease. On the basis of the X-ray structure of the domain of HLA-DQ2.5 bound to the DQ2.5-glia-α1a epitope, fifteen peptides were designed with the aim of lowering the epitope binding affinity, thus reducing the autoimmune response. Hydroxylation of Pro residues was proposed as a suitable functionalization given that both enzymatic and chemical synthetic methods are available. Then, a computational study on the effects of Pro hydroxylation on HLA-DQ2.5 binding was performed by molecular docking. A docking protocol able to reproduce the binding geometry of the known crystallographic complex was set up and applied to the designed DQ2.5-glia-α1a analogues. Among them, the one including four di-hydroxylated Pro residues was predicted to lower the binding affinity to the greatest extent. Therefore, the same functionalization was also computationally tested for other celiac disease relevant epitopes, DQ2.5-glia-α1b and DQ2.5-glia-α2, and their ability for inhibiting the binding to HLA-DQ2.5 was confirmed. On this basis, these hydroxylated peptides are expected to significantly affect the gluten activity involved in celiac disease and, after experimental validation, a synthetic method will be developed for introducing this gluten modification directly in flour. The proposed approach is a promising tool to study the binding of other gliadin and glutenin derived T-cell epitopes as well as their variants.
Department of Earth and Environmental Sciences, University of Milano-Bicocca, Piazza della Scienza 1, 20126 Milano, Italy. laura.bonati@unimib.it.
Domenico
D
Fraccalvieri
Stefano
S
Motta
Guido
G
Galliani
Linda
L
Cavaletti
Laura
L
Bonati
D002446:Celiac Disease / Q000276:immunology*; D015195:Drug Design; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D005903:Gliadin / Q000737:chemistry / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D010455:Peptides; D005903:Gliadin