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

Abstract

Tissue transglutaminase (TG2) is a Ca 2? -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.

IgG anti-tTG responses in different autoimmune conditions differ in their epitope targets and subclass usage

“…This is in consensus with the observation that autoimmune diseases -usually associated with a 'signature' antigen which may be intimately linked with disease pathogenesis or detection, -generally display autoantibody responses to a spectrum of self-antigens, some which may be shared by multiple diseases (Shoenfeld et al, 2007). The ubiquitous expression of tTG (Badarau et al, 2013) may partially explain its serial appearances as an antigen in a variety of autoimmune disorders. Proteins that are also the target of antibodies in multiple autoimmune diseases such as actin (Gueguen et al, 2006;Ishigatsubo et al, 1989;Musante et al, 2005) and RA33 (Isenberg et al, 1994;Steiner et al, 1996;El-Kased et al, 2009) tend to share a pattern of ubiquitous tissue distribution (Fritsch et al, 2002;Bertola et al, 2008), implying that immunity to these self-components may be secondary to an already established immune response against a primary, tissue-specific antigen.…”

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

“…TG2 is involved in a host of human diseases such as celiac disease, cancer, fibrosis, multiple sclerosis, and neurodegeneration . As a consequence, TG2 has become a potential therapeutic target for the treatment of these pathological conditions (Badarau et al, 2013a). Moreover, since TG2 is found both in the intra-and extracellular space, both targeted specificity for TG2 itself and specific targeting to a particular subcellular space are needed.…”

Syndecan-4 Knockout Leads to Reduced Extracellular Transglutaminase-2 and Protects against Tubulointerstitial Fibrosis

“…8 However, clinical application of anti-TG2 therapy has been hampered by the complexity to develop TG2-specific inhibitors due to a highly conserved catalytic core across the TG family, 10 with inhibition of factor XIIIa and the keratinocyte transglutaminase causing particular concern. 20 Consequently, elucidation of the mechanism whereby TG2 is released from cells has been an object of intense scrutiny, because TG2 is unconventionally secreted via a potentially unique non-Golgi route, 21,22 which may offer a specific interventional strategy to decrease extracellular TG2.…”