title: Development of Potent and Selective Tissue Transglutaminase Inhibitors: Their Effect on TG2 Function and Application in Pathological Conditions.
abstract: Potent-selective peptidomimetic inhibitors of tissue transglutaminase (TG2) were developed through a combination of protein-ligand docking and molecular dynamic techniques. Derivatives of these inhibitors were made with the aim of specific TG2 targeting to the intra- and extracellular space. A cell-permeable fluorescently labeled derivative enabled detection of in situ cellular TG2 activity in human umbilical cord endothelial cells and TG2-transduced NIH3T3 cells, which could be enhanced by treatment of cells with ionomycin. Reaction of TG2 with this fluorescent inhibitor in NIH3T3 cells resulted in loss of binding of TG2 to cell surface syndecan-4 and inhibition of translocation of the enzyme into the extracellular matrix, with a parallel reduction in fibronectin deposition. In human umbilical cord endothelial cells, this same fluorescent inhibitor also demonstrated a reduction in fibronectin deposition, cell motility, and cord formation in Matrigel. Use of the same inhibitor in a mouse model of hypertensive nephrosclerosis showed over a 40% reduction in collagen deposition.
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.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
authors.forename: Dan L
authors.initials: DL
authors.lastname: Rathbone
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Costanzi
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thibault
authors.affiliation: Aston Medical Research Institute, Aston Medical School, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
authors.forename: Colin E
authors.initials: CE
authors.lastname: Murdoch
authors.affiliation: Covalab France, 11 avenue Albert Einstein, 69100 Villeurbanne, France.
authors.forename: Said
authors.initials: S
authors.lastname: El Alaoui
authors.affiliation: Aston Medical Research Institute, Aston Medical School, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
authors.forename: Milda
authors.initials: M
authors.lastname: Bartkeviciute
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK. Electronic address: m.griffin@aston.ac.uk.
authors.forename: Martin
authors.initials: M
authors.lastname: Griffin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005355:Fibrosis / Q000188:drug therapy / Q000503:physiopathology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D041681:NIH 3T3 Cells; D009400:Nephrosclerosis / Q000188:drug therapy; D011485:Protein Binding / Q000187:drug effects; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D053671:Syndecan-4 / Q000378:metabolism; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D053671:Syndecan-4; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins