title: Imidazolium-based warheads strongly influence activity of water-soluble peptidic transglutaminase inhibitors.
abstract: New peptidic water-soluble inhibitors are reported. In addition to the carboxylate moiety, a new polar warhead was explored. Depending on the size of its substituents, the newly appended imidazolium scaffold designed to enhance the hydrophilic character of the inhibitors could induce a good inhibition for tissue transglutaminase (TG2) and blood coagulation factor XIIIa (FXIIIa). Correlated with the narrow tunnel that hosts the target catalytic cysteine residue, the various modulations suggest a bent conformation of the ligands as the binding pattern mode. Analogues in the dialkylsulfonium series were also tested and showed specificity for TG2 over FXIIIa.
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
authors.forename: Eduard
authors.initials: E
authors.lastname: Badarau
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mongeot
authors.forename: Russell
authors.initials: R
authors.lastname: Collighan
authors.forename: Dan
authors.initials: D
authors.lastname: Rathbone
authors.forename: Martin
authors.initials: M
authors.lastname: Griffin
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D019204:GTP-Binding Proteins; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012995:Solubility; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014867:Water / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D010455:Peptides; D014867:Water; C029899:imidazole; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: Coagulation factor XIIIa (FXIIIa); Dialkylsulfonium; Imidazolium warheads; Peptidic inhibitors; Tissue transglutaminase (TG2)