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  • Jefferson Adams
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    Scientists Testing Glutamate-Class Prolyl-endopeptidase for Celiac Disease Therapy

    Reviewed and edited by a celiac disease expert.

    Neprosin Shows the Marks of a Viable Therapeutic Glutenase

    Scientists Testing Glutamate-Class Prolyl-endopeptidase for Celiac Disease Therapy - Soaring. Image: CC BY-ND 2.0--gfpeck
    Caption: Soaring. Image: CC BY-ND 2.0--gfpeck

    Celiac.com 10/11/2022 - Enzymes that can break down gluten in the stomach before it gets to the gut are a potentially important therapy tool for people with celiac disease. In people with celiac disease, the digestion of gluten creates peptides, including the strongly immunogenic proline-rich 33-mer from wheat α-gliadin, that trigger auto-immune reactions in the gut, along with associated villi damage, when untreated. 

    Having a therapy that could reduce the abundance of the 33-mer in the small intestine could be very helpful to many people with celiac disease. Neprosin is the latest candidate. A team of researchers recently set out to test a glutamate-class prolyl-endopeptidase for celiac disease therapy.

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    The research team included 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. They are variously affiliated with the Proteolysis Laboratory at the Department of Structural Biology, Molecular Biology Institute of Barcelona (CSIC), Barcelona Science Park in Barcelona, Catalonia, Spain; the Section of Physiology; Department of Biochemistry and Physiology; Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Catalonia, Spain; and the Research Institute of Nutrition and Food Safety (INSA-UB), University of Barcelona in Barcelona, Catalonia, Spain.

    Neprosin from the pitcher plant is a reported prolyl endopeptidase. As part of their effort, the team produced recombinant neprosin, along with several mutants, and revealed that full-length neprosin is a zymogen, which is self-activated at gastric pH by the release of an all-β pro-domain via a pH-switch mechanism featuring a lysine plug. 

    The team describes the catalytic domain, in which the action occurs, as an atypical 7+8-stranded β-sandwich, with an extensive active-site cleft holding an unprecedented pair of catalytic glutamates. 

    The researchers found that neprosin quickly and effectively breaks down both gliadin and the 33-mer in vitro under gastric conditions. The action can be reversibly inactivated above pH 5. Moreover, administering gliadin and the neprosin zymogen together at the ratio 500:1 reduces the abundance of the 33-mer in the small intestine of mice by up to 90%. 

    A 90% reduction in the 33-mer means that a substantial reduction in the ability of the protein to trigger an immune response in people with celiac disease.

    Neprosin therefore represents a family of eukaryotic glutamate endopeptidases that meets the parameters for an effective therapeutic glutenase.

    The development of effective therapeutic glutenase products remains a top priority for many researchers, with the potential to benefit huge numbers of people with celiac disease, many of whom are subject to accidental gluten ingestion on a regular basis.

    Read more in Nature Communications volume 13, Article number: 4446 (2022)


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    somethings-gotta-give69

    Very interested 

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    Monoj3655

    This article is truly hopeful and promising to those of us with celiac disease.  I would love to be without stomach discomfort constantly if I eat something with gluten. Since being diagnosed with celiac, I have added yet another condition to my list.  I have FPIES to an ingredient called teff. 

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    trents

    There have been many attempts at a "celiac pill" that did not prove viable in the latter rounds of trial testing. And we were disappointed. So I have guarded optimism.

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    Jim Chris

    Interesting for sure but not sure for what the main purpose it is intended. If it is for only when I've accidentally ingested gluten or is it for daily use? I would love to see something that would allow me to be reasonably normal. But I hope all of the research someday leads to daily treatment. 

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    Monoj3655

    I have just returned from my second visit to the allergist.  He confirmed that I have FPIES ((food protein-induced enterocolitis syndrome) to a grain called Teff. Not only do I have celiac disease but now I need to be vigilant to make sure no gluten-free product contains teff.  He explained no case study exists regarding anyone having this particular syndrome since teff is fairly new to celiac patients. I actually could be 1 in a million.  I just wanted people to know, who have gastrointestinal issues that this could be an issue for them. There is no Epi-Pen to use for help, the only resort for me is a trip to the emergency room to rehydrate me. It is extremely scary.

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    trents
    30 minutes ago, Monoj3655 said:

    I have just returned from my second visit to the allergist.  He confirmed that I have FPIES ((food protein-induced enterocolitis syndrome) to a grain called Teff. Not only do I have celiac disease but now I need to be vigilant to make sure no gluten-free product contains teff.  He explained no case study exists regarding anyone having this particular syndrome since teff is fairly new to celiac patients. I actually could be 1 in a million.  I just wanted people to know, who have gastrointestinal issues that this could be an issue for them. There is no Epi-Pen to use for help, the only resort for me is a trip to the emergency room to rehydrate me. It is extremely scary.

    Actually, teff has been around as a wheat/barley/rye substitute grain for more than 20 years. I used it some right after I was diagnosed in about 2000-2001 so it has been available for at least that long. It's not one you hear about commonly, however. It has a mild, sweet taste as I recall. Kind of spendy, though.

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  • About Me

    Jefferson Adams

    Jefferson Adams is Celiac.com's senior writer and Digital Content Director. He earned his B.A. and M.F.A. at Arizona State University. His articles, essays, poems, stories and book reviews have appeared in numerous magazines, journals, and websites, including North American Project, Antioch Review, Caliban, Mississippi Review, Slate, and more. He is the author of more than 2,500 articles on celiac disease. His university coursework includes studies in science, scientific methodology, biology, anatomy, physiology, medicine, logic, and advanced research. He previously devised health and medical content for Colgate, Dove, Pfizer, Sharecare, Walgreens, and more. Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of numerous books, including "Cereal Killers" by Scott Adams and Ron Hoggan, Ed.D.

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