A study led by scientists at the Molecular Biology Institute of Barcelona (IBMB-CSIC), based at the Barcelona Science Park, has revealed that the neprosin molecule found in the digestive fluid of the carnivorous plant Nepenthes ventrata could counteract the toxic peptides that cause coeliac disease. The results of the study, published in Nature Communications, describe the molecule’s mechanism of activation, structure and most significant characteristics as a possible treatment for the disease.

The study was led by F. Xavier Gomis-Rüth and the first authors were Laura del Amo-Maestro and Soraia Mendes. Researchers from the University of Barcelona (UB) Faculty of Pharmacy and Food Science also participated, led by Francisco José Pérez Cano.

Inflammatory response in the intestines

Coeliac disease is triggered by 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. One of the most significant of these peptides is 33-mer, which is a fragment of alpha gliadin, a prolamin (plant glycoprotein) in wheat.

The 33-mer peptide can stand up to gastric acid in the stomach and make its way into the small intestine, where it crosses the intestinal mucosa. In people with coeliac disease, 33-mer binds with particular ease to a receptor in the immune system (human leukocyte antigen or HLA), which triggers an autoimmune and inflammatory response that leads to a whole series of manifestations characteristic of the disease.

The results from the teams in the IBMB-CSIC Proteolysis Laboratory and the UB Autoimmunity, Immunonutrition and Tolerance group show that neprosin can break down the 33-mer peptide before it reaches the intestine, so it could help prevent that autoimmune inflammatory response.

The scientists obtained recombinant cultures of human cells to get enough neprosin. They identified and determined the mechanism of activation for neprosin, as well as its ability to destroy gliadin and the 33-mer peptide.

In vivo experiments with a mouse model showed that the molecule effectively breaks down both structures in the stomach. They also resolved the three-dimensional structure and chemical mechanism of activation for neprosin and established characteristics like its thermal stability, pH profile and latency period, among others. These factors are very important for potential development of a preventive solution or treatment for the disease, neither of which currently exist.

Promising therapeutic path

“The studies we carried out have allowed us to verify that neprosin has huge potential for being developed as a medication, as it is much more active in the extreme conditions of digestion in the stomach than other proteolytic enzymes, known collectively as glutenases, currently being studied as candidates for therapeutic application, and meets all the a priori requirements for an effective glutenase,” notes CSIC researcher F. Xavier Gomis-Rüth. “We’re now moving into more specific assays to verify this potential before doing clinical trials and working with mutant molecules that could be even more efficient,” he adds.

The 33-mer peptide is one of the main causes of coeliac disease, as it is the result of breaking down a prolamin in wheat, one of the most widespread cereals on the market. Wheat is commonly found in an endless array of food, pharmaceutical and cosmetic products. “33-mer is the most toxic peptide generated from gliadin and we have to see if getting rid of it is enough to stop the physiopathological responses and manifestations of coeliac disease,” adds UB researcher Francisco José Pérez Cano.

› Reference article: Laura del Amo-Maestro , Soraia R. Mendes, Arturo Rodríguez-Banqueri , Laura Garzon-Flores, Marina Girbal, María José Rodríguez-Lagunas, Tibisay Guevara, Àngels Franch, Francisco J. Pérez-Cano, Ulrich Eckhard & F. Xavier Gomis-Rüth. Molecular and in vivo studies of a glutamate-class prolyl-endopeptidase for coeliac disease therapy. Nat Commun 13, 4446 (2022). DOI: https://doi.org/10.1038/s41467-022-32215-1

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