2006
DOI: 10.1021/ja056423o
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Inhibition of HLA-DQ2-Mediated Antigen Presentation by Analogues of a High Affinity 33-Residue Peptide from α2-Gliadin

Abstract: Human leukocyte antigen DQ2 is a class II major histocompatibility complex protein that plays a critical role in the pathogenesis of Celiac Sprue by binding to epitopes derived from dietary gluten and triggering the inflammatory response of disease-specific T cells. Inhibition of DQ2 mediated antigen presentation in the small intestinal mucosa of Celiac Sprue patients therefore represents a potentially attractive mode of therapy for this widespread but unmet medical need. Starting from a pro-inflammatory, prot… Show more

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Cited by 75 publications
(73 citation statements)
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“…Similarly, such compounds may be of use for the prevention of type I diabetes. The first steps toward generating such blocking compounds have already been undertaken (27), but it is clear that to obtain a therapeutically useful agent a substantial improvement will be required. The natural ligands for HLA-DQ2 identified in the present study provide new insight into peptidebinding properties of this molecule and novel templates, both of which are likely to be of importance for the development of an effective HLA-DQ2 blocker.…”
Section: Discussionmentioning
confidence: 99%
“…Similarly, such compounds may be of use for the prevention of type I diabetes. The first steps toward generating such blocking compounds have already been undertaken (27), but it is clear that to obtain a therapeutically useful agent a substantial improvement will be required. The natural ligands for HLA-DQ2 identified in the present study provide new insight into peptidebinding properties of this molecule and novel templates, both of which are likely to be of importance for the development of an effective HLA-DQ2 blocker.…”
Section: Discussionmentioning
confidence: 99%
“…D8mer and 33mer peptides were synthesized by using tert-butoxy-carbonyl/O-(benzotriazol-1-yl)-N,N,NЈ,NЈ-tetramethyluronium hexafluorophosphate chemistry on solid-phase N-R-t-Boc-L-aminoacyl phenylacetamidomethyl resin as described previously (Xia et al, 2006;Bethune et al, 2009a,b). The membrane-permeable myosin light chain kinase (MLCK) inhibitor, PIK, was synthesized by using a fluorenylmethyloxycarbonyl/O-(benzotriazol-1-yl)-N,N,NЈ,NЈ-tetramethyluronium hexafluorophosphate chemistry on solid-phase fluorenylmethyloxycarbonyl-Nε-Boc-L-lysine-aminomethyl rink amide aminomethyl resin as described previously (Zolotarevsky et al, 2002).…”
Section: Methodsmentioning
confidence: 99%
“…Based on the central importance of HLA-DQ2 and HLA-DQ8 for the development of CD, methods that attempt to block the binding of disease-activating "gluten" peptides to HLA-DQ2 or HLA-DQ8 seem an obvious approach (91). Nonetheless, potential pitfalls exist in the design of and the means of administering such "blockers."…”
Section: Figurementioning
confidence: 99%