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J Am Chem Soc. 2015 Oct 14;137(40):13106-13. doi: 10.1021/jacs.5b08325. Epub 2015 Sep 29.

Engineering of Kuma030: A Gliadin Peptidase That Rapidly Degrades Immunogenic Gliadin Peptides in Gastric Conditions.

Author information

1
Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
2
Departments of Chemistry, Biochemistry, and Molecular Medicine, University of California-Davis , Davis, California 95616, United States.
3
Institute of Food Science-CNR, Avellino, Italy.
4
Institute of Protein Biochemistry-CNR, Naples, Italy.
5
Department of Gastroenterology, University of Washington Medical Center , Seattle, Washington 98195, United States.
6
Department of Molecular Biology & Biochemistry, Rutgers University , Piscataway, New Jersey 08901, United States.

Abstract

Celiac disease is characterized by intestinal inflammation triggered by gliadin, a component of dietary gluten. Oral administration of proteases that can rapidly degrade gliadin in the gastric compartment has been proposed as a treatment for celiac disease; however, no protease has been shown to specifically reduce the immunogenic gliadin content, in gastric conditions, to below the threshold shown to be toxic for celiac patients. Here, we used the Rosetta Molecular Modeling Suite to redesign the active site of the acid-active gliadin endopeptidase KumaMax. The resulting protease, Kuma030, specifically recognizes tripeptide sequences that are found throughout the immunogenic regions of gliadin, as well as in homologous proteins in barley and rye. Indeed, treatment of gliadin with Kuma030 eliminates the ability of gliadin to stimulate a T cell response. Kuma030 is capable of degrading >99% of the immunogenic gliadin fraction in laboratory-simulated gastric digestions within physiologically relevant time frames, to a level below the toxic threshold for celiac patients, suggesting great potential for this enzyme as an oral therapeutic for celiac disease.

PMID:
26374198
PMCID:
PMC4958374
DOI:
10.1021/jacs.5b08325
[Indexed for MEDLINE]
Free PMC Article

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