Treatment for celiac disease, closer every day – El Debate

A study led by scientists from the Barcelona Institute of Molecular Biology (IBMB-CSIC) has identified a molecule that could counteract the effect of toxic peptides that cause celiac disease, a chronic autoimmune disease that is triggered in response to gluten intake. The molecule studied is neprosin, which is found naturally in the digestive fluid of the carnivorous plant Nepenthes ventrata. According to the work led by the researcher F. Xavier Gomis-Rüth ​​and whose first signatories are the researchers Laura del Amo -Maestro and Soraia Mendes, all from the IBMB-CSIC, neprosin is a promising treatment option for celiac disease. The authors have deciphered the mechanism of action of the molecule, its structure, as well as its most relevant characteristics for a possible treatment of the disease. The work, published in Nature Communications, also includes the participation of researchers from the Faculty of Pharmacy and Food Sciences of the University of Barcelona (UB), led by Francisco José Pérez Cano. What causes celiac disease What triggers celiac disease are several prolamin-rich proteins found in cereals. When these proteins are digested in the stomach, they break down into smaller ones (peptides) that can be toxic. Among these peptides, one of the most relevant is the 33-mer, which is a fragment of alpha-gliadin, a prolamin (plant glycoprotein) from wheat. The 33-mer peptide is able to resist the gastric acids of the stomach and reach the small intestine and, once there, it crosses the intestinal mucosa. In the case of people with celiac disease, the 33-mer binds with particular ease to an immune system receptor (the human leukocyte antigen or HLA), which triggers an autoimmune and inflammatory response that ends up causing a whole series of characteristic manifestations of celiac disease. the illness. The results of the teams from the Proteolysis Group of the IBMB-CSIC and the Autoimmunity, Immunonutrition and Tolerance group of the UB show that neprosin can degrade the 33-mer peptide before it reaches the intestine, which could prevent this autoimmune inflammatory response. Scientists have grown recombinant cultures of human cells to get enough neprosin. They have identified and determined the mechanism of action of neprosin, as well as its ability to destroy gliadin and the 33-mer peptide. In vivo experiments in a murine model show that the molecule is effective in degrading both structures in the stomach. They have also resolved the three-dimensional structure and the chemical mechanism of action of neprosin and have established characteristics such as its thermal stability, its pH profile, and its latency period, among others. These factors are very important for a possible development of the prevention or treatment, until now non-existent, of the disease. We have verified that neprosin has enormous potential to be developed as a drugScientists from the IBMB-CSIC«A promising pathway is molecules that destroy toxic peptides, and that can be administered orally, similar to the lactase tablets that are taken those who are lactose intolerant”, explain the scientists. Such a treatment should contain a molecule capable of breaking down toxic peptides and be harmless to the intestine; it should be efficient enough to degrade a fair amount of toxic peptides at reasonable doses; and it should be active before passing into the intestine, the researchers say. Neprosin has enormous potential to be developed as a medicine«The studies we have carried out have allowed us to verify that neprosin has enormous potential to be developed as a medicine, since it is much more active in the extreme conditions of digestion in the stomach than other candidate proteolytic enzymes currently under study, collectively called glutenases, for their therapeutic application, and it meets all the characteristics that are required a priori for an efficient glutenase”, points out CSIC researcher F. Xavier Gomis-Rüth. “We are now going to move on to more specific tests to verify this potential before moving on to clinical trials and working with mutant molecules that may be even more efficient,” he adds. What causes celiac disease The 33-mer peptide is one of the main causes of celiac disease. celiac disease, since it is generated by the degradation of a wheat prolamin, one of the most widespread cereals on the market. It is easy to find wheat gluten in innumerable food, pharmaceutical and cosmetic products… “33-mer is the most toxic peptide of those generated from gliadin and it remains to be seen whether its eradication would be enough to eliminate the manifestations and responses pathophysiology of celiac disease”, adds Francisco José Pérez Cano, researcher at the UB.