Format

Send to

Choose Destination
Chem Biol. 2015 Oct 22;22(10):1347-61. doi: 10.1016/j.chembiol.2015.08.013. Epub 2015 Oct 9.

Development of Potent and Selective Tissue Transglutaminase Inhibitors: Their Effect on TG2 Function and Application in Pathological Conditions.

Author information

1
School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
2
Aston Medical Research Institute, Aston Medical School, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
3
Covalab France, 11 avenue Albert Einstein, 69100 Villeurbanne, France.
4
School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK. Electronic address: m.griffin@aston.ac.uk.

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.

PMID:
26456735
DOI:
10.1016/j.chembiol.2015.08.013
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center