A study led by scientists from the Barcelona Institute of Molecular Biology (IBMB-CSIC) has identified a molecule that could counteract the effect of the toxic peptides that cause celiac diseasea chronic autoimmune disease that is triggered in response to gluten ingestion.
It’s about the neprosinfound naturally in the digestive fluid of the carnivorous plant Nepenthes venrata. The authors have deciphered the mechanism of action, structure and most relevant characteristics of the molecule with a view to a possible treatment of the pathology. The study has been published in Nature Communications.
An inflammatory response in the gut
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 (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 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 that can be toxic.
The 33-mer is able to resist the gastric acids of the stomach, reach the small intestine and, once there, cross the intestinal mucosa. In the case of people with celiac disease, this peptide binds especially easily to a immune system receptor (the human leukocyte antigen or HLA), which triggers an autoimmune and inflammatory response that gives rise to a whole 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 this autoimmune inflammatory response.
The role of neprosin
Scientists have obtained recombinant human cell cultures to get enough neprosin. They have identified and determined its mechanism of action, as well as its ability to destroy gliadin and the 33-mer peptide. experiments live in a mouse model show that the molecule is effective 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. One promising avenue is molecules that destroy toxic peptides, and that can be administered orally, similar to the lactase tablets taken by people who are lactose intolerant, the study authors explain.
Future therapeutic applications
Such a treatment should contain a molecule capable of breaking down toxic peptides and be harmless to the intestinebe efficient enough to break down a fair amount of toxic peptides at reasonable doses, and should be active before passing into the gut, the researchers say.
“We have been able to verify that neprosin has enormous potential 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 for therapeutic application,” he points out. F. Xavier Gomis-Rüth.
We have been able to verify that neprosin has enormous potential as a medicine, since it is much more active in the extreme conditions of digestion in the stomach than other candidate enzymes currently under study.
F. Xavier Gomis-Rüth
“We are now going to carry out 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.
For its part, Francisco Jose Perez Canoa researcher at the University of Barcelona and another of the authors, comments that “the 33-mer is the most toxic peptide of those generated from gliadin and it remains to be seen whether its eradication would suffice to eliminate the pathophysiological manifestations and responses of celiac disease”.
East Article was originally published in Agencia Sinc, the scientific news agency of the Spanish Foundation for Science and Technology
The enlightened ones of gluten
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