Structure-based design of alpha-amido aldehyde containing gluten peptide analogues as modulators of HLA-DQ2 and transglutaminase 2.
Complete, life-long exclusion of gluten containing foods from the diet is the only available treatment for celiac sprue, a widespread immune disease of the small intestine. Investigations into the molecular pathogenesis of celiac sprue have identified the major histocompatibility complex protein HLA-DQ2 and the multi-functional enzyme transglutaminase 2 as potential pharmacological targets. Based upon the crystal structure of HLA-DQ2, we rationally designed an aldehyde-functionalized, gluten peptide analogue as a tight-binding HLA-DQ2 ligand. Aldehyde-bearing gluten peptide analogues were also designed as high-affinity, reversible inhibitors of transglutaminase 2. By varying the side-chain length of the aldehyde-functionalized amino acid, we found that the optimal transglutaminase 2 inhibitor was 5 methylene units in length, 2 carbon atoms longer than its natural glutamine substrate.
Siegel
Matthew
M
Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
Xia
Jiang
J
Khosla
Chaitan
C
D000447:Aldehydes / Q000737:chemistry* / Q000276:immunology; D000577:Amides / Q000737:chemistry* / Q000276:immunology; D017951:Antigen Presentation; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005720:Gamma Rays; D005983:Glutens / Q000737:chemistry* / Q000276:immunology; D006683:HLA-DQ Antigens / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000447:Aldehydes; D000577:Amides; D004791:Enzyme Inhibitors; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D008024:Ligands; D010446:Peptide Fragments; D005983:Glutens; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins