Cyclic and dimeric gluten peptide analogues inhibiting DQ2-mediated antigen presentation in celiac disease.
Celiac disease is an immune mediated enteropathy elicited by gluten ingestion. The disorder has a strong association with HLA-DQ2. This HLA molecule is involved in the disease pathogenesis by presenting gluten peptides to T cells. Blocking the peptide-binding site of DQ2 may be a way to treat celiac disease. In this study, two types of peptide analogues, modeled after natural gluten antigens, were studied as DQ2 blockers. (a) Cyclic peptides. Cyclic peptides containing the DQ2-alphaI gliadin epitope LQPFPQPELPY were synthesized with flanking cysteine residues introduced and subsequently crosslinked via a disulfide bond. Alternatively, cyclic peptides were prepared with stable polyethylene glycol bridges across internal lysine residues of modified antigenic peptides such as KQPFPEKELPY and LQLQPFPQPEKPYPQPEKPY. The effect of cyclization as well as the length of the spacer in the cyclic peptides on DQ2 binding and T cell recognition was analyzed. Inhibition of peptide-DQ2 recognition by the T cell receptor was observed in T cell proliferation assays. (b) Dimeric peptides. Previously we developed a new type of peptide blocker with much enhanced affinity for DQ2 by dimerizing LQLQPFPQPEKPYPQPELPY through the lysine side chains. Herein, the effect of linker length on both DQ2 binding and T cell inhibition was investigated. One dimeric peptide analogue with an intermediate linker length was found to be especially effective at inhibiting DQ2 mediated antigen presentation. The implications of these findings for the treatment of celiac disease are discussed.
Department of Chemistry, Stanford University, Stanford, CA 94305-5025, USA.
Jiang
J
Xia
Elin
E
Bergseng
Burkhard
B
Fleckenstein
Matthew
M
Siegel
Chu-Young
CY
Kim
Chaitan
C
Khosla
Ludvig M
LM
Sollid
D002446:Celiac Disease / Q000276:immunology* / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D005983:Glutens / Q000737:chemistry*; D006683:HLA-DQ Antigens / Q000737:chemistry* / Q000276:immunology*; D020128:Inhibitory Concentration 50; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D004220:Disulfides; D006683:HLA-DQ Antigens; D010455:Peptides; D005983:Glutens