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

Eduard Badarau, Russell J. Collighan, Martin Griffin*

*Corresponding author for this work

Research output: Contribution to journalArticle

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. © 2011 Springer-Verlag.

Original languageEnglish
Pages (from-to)119-127
Number of pages9
JournalAmino Acids
Volume44
Issue number1
Early online date13 Dec 2011
DOIs
Publication statusPublished - Jan 2013

Fingerprint

Biological Phenomena
Transglutaminases
Enzyme Activation
Huntington Disease
Celiac Disease
Enzymes
Structure-Activity Relationship
Guanosine Triphosphate
Glutamine
Cystic Fibrosis
Lysine
Multiple Sclerosis
Parkinson Disease
Alzheimer Disease
Fibrosis
Therapeutics
Chemical activation
Derivatives
Neoplasms
Proteins

Keywords

  • inhibitors
  • structure-activity relationships (SAR)
  • TG2
  • tissue transglutaminase

Cite this

@article{6f2edbb7da824bbe84bd4a28ef69a280,
title = "Recent advances in the development of tissue transglutaminase (TG2) inhibitors",
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. {\circledC} 2011 Springer-Verlag.",
keywords = "inhibitors, structure-activity relationships (SAR), TG2, tissue transglutaminase",
author = "Eduard Badarau and Collighan, {Russell J.} and Martin Griffin",
year = "2013",
month = "1",
doi = "10.1007/s00726-011-1188-4",
language = "English",
volume = "44",
pages = "119--127",
journal = "Amino Acids",
issn = "0939-4451",
publisher = "Springer",
number = "1",

}

Recent advances in the development of tissue transglutaminase (TG2) inhibitors. / Badarau, Eduard; Collighan, Russell J.; Griffin, Martin.

In: Amino Acids, Vol. 44, No. 1, 01.2013, p. 119-127.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Recent advances in the development of tissue transglutaminase (TG2) inhibitors

AU - Badarau, Eduard

AU - Collighan, Russell J.

AU - Griffin, Martin

PY - 2013/1

Y1 - 2013/1

N2 - 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. © 2011 Springer-Verlag.

AB - 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. © 2011 Springer-Verlag.

KW - inhibitors

KW - structure-activity relationships (SAR)

KW - TG2

KW - tissue transglutaminase

UR - http://www.scopus.com/inward/record.url?scp=84871981788&partnerID=8YFLogxK

U2 - 10.1007/s00726-011-1188-4

DO - 10.1007/s00726-011-1188-4

M3 - Article

C2 - 22160259

VL - 44

SP - 119

EP - 127

JO - Amino Acids

JF - Amino Acids

SN - 0939-4451

IS - 1

ER -