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Recent advances in the development of tissue transglutaminase (TG2) inhibitors

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Abstract

Tissue transglutaminase (TG2) is a Ca2+-dependent enzyme and probably the most ubiquitously expressed member of the mammalian transglutaminase family. TG2 plays a number of important roles in a variety of biological processes. Via its transamidating function, it is responsible for the cross-linking of proteins by forming isopeptide bonds between glutamine and lysine residues. Intracellularly, Ca2+ activation of the enzyme is normally tightly regulated by the binding of GTP. However, upregulated levels of TG2 are associated with many disease states like celiac sprue, certain types of cancer, fibrosis, cystic fibrosis, multiple sclerosis, Alzheimer’s, Huntington’s and Parkinson’s disease. Selective inhibitors for TG2 both cell penetrating and non-cell penetrating would therefore serve as novel therapeutic tools for the treatment of these disease states. Moreover, they would provide useful tools to fully elucidate the cellular mechanisms TG2 is involved in and help comprehend how the enzyme is regulated at the cellular level. The current paper is intended to give an update on the recently discovered classes of TG2 inhibitors along with their structure–activity relationships. The biological properties of these derivatives, in terms of both activity and selectivity, will also be reported in order to translate their potential for future therapeutic developments.

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Abbreviations

TGase:

Transglutaminase

SAR:

Structure–activity relationship

HYD:

Hydrophobic

HBA:

Hydrogen bond acceptor

GTP:

Guanosine triphosphate

GDH:

Glutamate dehydrogenase

5-BP:

5-Biotinamidopentylamine

tBoc:

tert-Butyloxycarbonyl

Cbz:

Benzyloxycarbonyl

Fmoc:

Fluorenylmethyloxycarbonyl

Ac:

Acetyl

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Acknowledgments

E.B. is a research fellow with the support of the Marie Curie Seventh Framework Programme Industry-Academia Partnerships and Pathways (IAPP), TRANSCOM: “The Commercialisation of Transglutaminase” (FP7 No: 251506).

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Authors and Affiliations

  1. School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK

    E. Badarau, R. J. Collighan & M. Griffin

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  1. E. Badarau
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  2. R. J. Collighan
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  3. M. Griffin
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Correspondence to M. Griffin.

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Badarau, E., Collighan, R.J. & Griffin, M. Recent advances in the development of tissue transglutaminase (TG2) inhibitors. Amino Acids 44, 119–127 (2013). https://doi.org/10.1007/s00726-011-1188-4

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  • DOI: https://doi.org/10.1007/s00726-011-1188-4

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