Potential of transglutaminase 2 as a therapeutic target.

IMPORTANCE OF THE FIELD: Increased expression and activity of transglutaminase 2 - a calcium-dependent enzyme which catalyzes protein cross-linking, polyamination or deamidation at selective glutamine residues - are involved in the etiopathogenesis of several pathological conditions, such as neurodegenerative disorders, autoimmune diseases and inflammatory diseases. Inhibition of enzyme activity has potential for therapeutic management of these diseases. AREAS COVERED IN THIS REVIEW: The major results achieved in the last twelve years of research in the field of inhibition of tranglutaminase activity using cell cultures as well as in vivo models of high-social-impact or widespread diseases, such as CNS neurodegenerative disorders, celiac sprue, cancer and fibrotic diseases. WHAT THE READER WILL GAIN: Beneficial effects of enzyme activity inhibition have been observed in neurodegeneration and fibrosis in vivo models by delivery of the competitive inhibitor cystamine and more recently designed inhibitors, such as thiomidaziolium or norleucine derivatives, which irreversibly bind the active site cysteine residue. Transglutaminase 2 targeting with specific antibodies has also been shown to be a promising tool for celiac disease treatment. TAKE HOME MESSAGE: New insights from transglutaminase inhibition studies dealing with side effects of in vivo administration of pan-transglutaminase inhibitors will help in design of novel therapeutic approaches to various diseases.