Also known as coeliac sprue, gluten intolerance is a widely prevalent genetically determined condition that affects almost 1% of the population. At present, there are no therapeutic agents for this disease, and the only known treatment is a strict, lifelong gluten-free diet. In the March issue of Chemistry and Biology, new research describes the design of proteolytically stable peptide inhibitors of the enzyme involved in the production of autoantigens from gluten, tissue transglutaminase (TGM2).

Ingestion of gluten proteins, from the common food grains wheat, rye, and barley, by coeliac patients results in the flattening of the epithelial villous lining of the small intestine, which leads to malabsorption of nutrients, weight loss and a whole host of other symptoms, including intestinal malignancies. Several short proline- and glutamine-rich sequences, identified from wheat gluten, activate gluten-responsive T cells extracted from coeliac patients, but not those from control individuals. Interestingly, most of these peptides are also substrates of TGM2, which is also known to be the principal focus of the auto-antibody response in coeliac sprue.

Selective inhibition of TGM2 might be a useful therapeutic strategy for avoiding the immunotoxic response to dietary gluten, an idea supported by reports that mice deficient in TGM2 are viable and phenotypically normal. In the design of one of the inhibitors, Hausch et al. replaced the glutamine in the immunodominant gluten peptide with a 6-diazo-5-oxo-norleucine residue to obtain a highly active and tight-binding inhibitor of TGM2 with low cellular toxicity. The inhibitor inactivated TGM2 by binding within the enzyme's active site, and so could interfere with the disease pathogenesis. Experiments demonstrated that the inhibitor interfered with enzyme activity in cultured cells, and effectively inhibited TGM2-mediated differentiation of an established cell model of intestinal enterocyte maturation.

This potent and selective TGM2 inhibitor will be a valuable tool for further research into coeliac disease, although whether it will be effective in humans remains to be seen. Interestingly, aberrant TGM2 activity is believed to play a role in neurological disorders such as Alzheimer's, Parkinson's and Huntington's diseases, indicating potentially wider use for any ultimately approved TGM2 inhibitors.