Design, synthesis, and evaluation of gluten peptide analogs as selective inhibitors of human tissue transglutaminase.
Recent studies have implicated a crucial role for tissue transglutaminase (TG2) in the pathogenesis of Celiac Sprue, a disorder of the small intestine triggered in genetically susceptible individuals by dietary exposure to gluten. Proteolytically stable peptide inhibitors of human TG2 were designed containing acivicin or alternatively 6-diazo-5-oxo-norleucine (DON) as warheads. In biochemical and cell-based assays, the best of these inhibitors, Ac-PQP-(DON)-LPF-NH(2), was considerably more potent and selective than other TG2 inhibitors reported to date. Selective pharmacological inhibition of extracellular TG2 should be useful in exploring the mechanistic implications of TG2-catalyzed modification of dietary gluten, a phenomenon of considerable relevance in Celiac Sprue.
Hausch
Felix
F
Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
Halttunen
Tuula
T
Mäki
Markku
M
Khosla
Chaitan
C
D000818:Animals; D002478:Cells, Cultured; D003980:Diazooxonorleucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018698:Glutamic Acid / Q000737:chemistry; D005983:Glutens / Q000737:chemistry*; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013329:Structure-Activity Relationship; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D004791:Enzyme Inhibitors; D007555:Isoxazoles; D010455:Peptides; D003980:Diazooxonorleucine; D018698:Glutamic Acid; D005983:Glutens; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; C006303:acivicin