Development of potent and selective tissue transglutaminase inhibitors:their effect on TG2 function and application in pathological conditions


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.

Publication DOI:
Divisions: Life & Health Sciences > Biosciences
Life & Health Sciences > Pharmacy
Life & Health Sciences
Life & Health Sciences > Cellular and Molecular Biomedicine
Aston Medical School
Life & Health Sciences > Chronic and Communicable Conditions
Life & Health Sciences > Cell & Tissue Biomedical Research
Additional Information: © 2015, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Cell Press papers are freely available starting 12 months after publication. Supplementary Information:
Uncontrolled Keywords: irreversible tissue transglutaminase inhibitors,Biochemistry,Drug Discovery,Molecular Biology,Clinical Biochemistry,Molecular Medicine,Pharmacology
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2015-10-22
Published Online Date: 2015-10-09
Authors: Badarau, Eduard
Wang, Zhuo ( 0000-0002-2212-8318)
Rathbone, Dan L. ( 0000-0003-4732-4662)
Costanzi, Andrea
Thibault, Thomas
Murdoch, Colin E. ( 0000-0002-0274-819X)
El Alaoui, Said
Bartkeviciute, Milda
Griffin, Martin

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