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

Clancey Wolf, Justin Siegel, Christine Tinberg, Alessandra Camarca, Carmen Gianfrani, Shirley Paski, Rongjin Guan, Gaetano Montelione, David Baker, Ingrid S. Pultz

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)13106-13113
Number of pages8
JournalJournal of the American Chemical Society
Volume137
Issue number40
DOIs
StatePublished - Oct 14 2015

Fingerprint

Gliadin
Peptides
Stomach
Peptide Hydrolases
Celiac Disease
Molecular modeling
T-cells
Poisons
Enzymes
Abdomen
Proteins
Acids
Endopeptidases
Glutens
Hordeum
Oral Administration
Digestion
Catalytic Domain
Therapeutics
Inflammation

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Engineering of Kuma030 : A Gliadin Peptidase That Rapidly Degrades Immunogenic Gliadin Peptides in Gastric Conditions. / Wolf, Clancey; Siegel, Justin; Tinberg, Christine; Camarca, Alessandra; Gianfrani, Carmen; Paski, Shirley; Guan, Rongjin; Montelione, Gaetano; Baker, David; Pultz, Ingrid S.

In: Journal of the American Chemical Society, Vol. 137, No. 40, 14.10.2015, p. 13106-13113.

Research output: Contribution to journalArticle

Wolf, C, Siegel, J, Tinberg, C, Camarca, A, Gianfrani, C, Paski, S, Guan, R, Montelione, G, Baker, D & Pultz, IS 2015, 'Engineering of Kuma030: A Gliadin Peptidase That Rapidly Degrades Immunogenic Gliadin Peptides in Gastric Conditions', Journal of the American Chemical Society, vol. 137, no. 40, pp. 13106-13113. https://doi.org/10.1021/jacs.5b08325
Wolf, Clancey ; Siegel, Justin ; Tinberg, Christine ; Camarca, Alessandra ; Gianfrani, Carmen ; Paski, Shirley ; Guan, Rongjin ; Montelione, Gaetano ; Baker, David ; Pultz, Ingrid S. / Engineering of Kuma030 : A Gliadin Peptidase That Rapidly Degrades Immunogenic Gliadin Peptides in Gastric Conditions. In: Journal of the American Chemical Society. 2015 ; Vol. 137, No. 40. pp. 13106-13113.
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