Design, Synthesis, and Evaluation of Dihydroisoxazole Analogs as Irreversible Inhibitors of Tissue Transglutaminase

1 At 76 kD with 686 amino acids, tissue transglutaminase (TG2) is a calcium-dependent multifunctional enzyme that catalyzes post-translational modification of specific glutamine residues. TG2 is a ubiquitous enzyme functioning at various cell locations and plays important roles in many cellular processes including cell death, cell movement, adhesion, and proliferation. Even though TG2 possesses many protective functions in humans, its defective expression can lead to diverse clinical disorders. Neurodegenerative disorders, such as Huntington’s, Alzheimer’s, and Parkinson’s diseases, are linked with TG2-catalyzed transamidation reactions whereas diseases like Coeliac Sprue are related to the deamidation activity of the enzyme. Despite its importance in mammalian biology, animal study has shown that ablation of both copies of the TG2 gene does not result in an embryonic lethal phenotype. In fact, TG2-/TG2animals are viable with normal size and weight and are born with Mendelian frequency1. A possible explanation for this paradox is that other types of transglutaminases might compensate for the absence of TG2 in mammalian tissues2. Although the knockout animals show some type of impaired wound healing, autoimmunity, and diabetes, the relatively low toxic effect of TG2 deletion is clear from this study. In addition, it can be inferred that TG2 inhibitors are potential pharmacological agents to treat some of the diseases described above. Coeliac Sprue is of particular interest; even though coeliac disease is prevalent among Caucasians, affecting 1 in every 200 individuals, no effective treatments have been developed other than strict, lifelong gluten-free diet. This malabsorption syndrome caused by intolerance to ingested gluten proteins from common food grains like wheat, rye, and barley is characterized by total atrophy of villi and flattening of the mucosa from chronic inflammaDesign, Synthesis, and Evaluation of Dihydroisoxazole Analogs as Irreversible Inhibitors of Tissue Transglutaminase Biology