And work led by scientists from the Institute of Molecular Biology of Barcelona (IBMB-CSIC) has identified a molecule that could counteract the effect of toxic peptides that cause celiac diseasea chronic autoimmune disease triggered in response to gluten ingestion.
It is don’t asknaturally present in the digestive liquid of the carnivorous plant Nepenthes ventrata. The authors have deciphered the mechanism of action, the structure and the most relevant characteristics of the molecule with a view to a possible treatment of the pathology. The study was published in Nature Communication.
An inflammatory response in the gut
Celiac disease is triggered by various prolamin-rich proteins found in cereals. When digested in the stomach, they break down into smaller ones (peptides) which can be toxic. Among these peptides, one of the most relevant is 33-mer, which is a fragment of alpha-gliadin, a wheat glycoprotein.
Celiac disease is triggered by various prolamin-rich proteins found in cereals. When these are digested in the stomach, they break down into smaller ones which can be toxic.
33-mer is able to resist gastric acids from the stomach, reach the small intestine and, once there, pass through the intestinal mucosa. In the case of people with celiac disease, this peptide binds particularly easily to a immune system receptor (the human leukocyte antigen or HLA), which triggers an autoimmune and inflammatory response giving rise to a series of characteristic manifestations of the disease.
The results show that neprosin can degrade the 33-mer peptide before it reaches the intestine, which could prevent it. autoimmune inflammatory response.
The role of neprosin
The scientists got cultures of recombinant human cells to get enough neprosin. They identified and determined its mechanism of action, as well as its ability to destroy gliadin and the 33-mer peptide. experiences live in a mouse model show that the molecule is effective degrading both structures in the stomach.
They also solved the three-dimensional structure and mechanism of chemical action of neprosin and established characteristics such as its thermal stability, pH profile and lag period, among others.
These factors are very important for a possible development of prevention or treatment, so far non-existent, of the disease. One promising avenue is through molecules that destroy toxic peptides and can be administered orally, such as lactase tablets taken by people with lactose intolerance, the study authors explain.
Future therapeutic applications
Such a treatment must contain a molecule capable of degrading toxic peptides and be harmless to the intestinebe efficient enough to break down a fair amount of toxic peptides in reasonable doses, and should be active before passing through the gut, the researchers say.
“We were able to verify that neprosin has enormous potential as a drug, since it is much more active under the extreme conditions of digestion in the stomach than other candidate proteolytic enzymes currently under study for therapeutic application” , he says. Br Xavier Gomis-Rüth.
We were able to verify that neprosin has enormous potential as a drug, since it is much more active in the extreme conditions of digestion in the stomach than other candidate enzymes currently under study.
Br Xavier Gomis-Rüth
— CSIC
“We will now carry out more specific tests to verify this potential before moving on to clinical trials and working with mutant molecules that could be even more effective,” he adds.
For its part, Francisco Jose Perez Canoresearcher at the University of Barcelona and another of the authors, comments that “33-mer is the most toxic peptide of those generated from gliadin and it remains to be seen whether its eradication would be sufficient to eliminate the pathophysiological manifestations and the celiac disease responses”.
He is Article was originally published in Agencia Sinc, the science news agency of the Spanish Foundation for Science and Technology
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