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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.
AuthorsEduard Badarau, Zhuo Wang, Dan L Rathbone, Andrea Costanzi, Thomas Thibault, Colin E Murdoch, Said El Alaoui, Milda Bartkeviciute, Martin Griffin
JournalChemistry & biology (Chem Biol) Vol. 22 Issue 10 Pg. 1347-61 (Oct 22 2015) ISSN: 1879-1301 [Electronic] United States
PMID26456735 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Ltd. All rights reserved.
Chemical References
  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Syndecan-4
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins
Topics
  • Animals
  • Blotting, Western
  • Endothelial Cells (drug effects, enzymology)
  • Enzyme Activation (drug effects)
  • Enzyme Inhibitors (chemistry, pharmacology, therapeutic use)
  • Fibrosis (drug therapy, physiopathology)
  • GTP-Binding Proteins (antagonists & inhibitors, metabolism)
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • NIH 3T3 Cells
  • Nephrosclerosis (drug therapy)
  • Protein Binding (drug effects)
  • Protein Glutamine gamma Glutamyltransferase 2
  • Small Molecule Libraries (chemistry, pharmacology)
  • Syndecan-4 (metabolism)
  • Transglutaminases (antagonists & inhibitors, metabolism)

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