Fighting Celiac Disease: Improvement of pH Stability of Cathepsin L In Vitro by Computational Design

Fighting Celiac Disease: Improvement of pH Stability of Cathepsin L In Vitro by Computational Design

Roughly 1% of the global population is susceptible to celiac disease (CD)-inheritable autoimmune inflammation of the small intestine caused by intolerance to gliadin proteins present in wheat, rye, and barley grains, and called gluten in wheat. Classical treatment is a life-long gluten-free diet, wh...

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Bibliographic Details
Published in:International journal of molecular sciences Vol. 24; no. 15; p. 12369
Main Authors: Chugunov, Anton O, Dvoryakova, Elena A, Dyuzheva, Maria A, Simonyan, Tatyana R, Tereshchenkova, Valeria F, Filippova, Irina Yu, Efremov, Roman G, Elpidina, Elena N
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 01-08-2023
MDPI
Subjects:
acid stability
Acidification
cathepsin L
Cathepsins
Celiac disease
Disease susceptibility
Enzymes
Glutamine
Gluten
gluten intolerance
glutenase
Grain
Hydrogen-ion concentration
Immune response
Molecular dynamics
Peptides
post-glutamine cleaving peptidase
Proline
Proteins
Simulation
Russia
glutenase
gluten intolerance
celiac disease
Tribolium castaneum
post-glutamine cleaving peptidase
acid stability
cathepsin L
molecular dynamics
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Summary:Roughly 1% of the global population is susceptible to celiac disease (CD)-inheritable autoimmune inflammation of the small intestine caused by intolerance to gliadin proteins present in wheat, rye, and barley grains, and called gluten in wheat. Classical treatment is a life-long gluten-free diet, which is constraining and costly. An alternative approach is based upon the development and oral reception of effective peptidases that degrade in the stomach immunogenic proline- and glutamine-rich gliadin peptides, which are the cause of the severe reaction in the intestine. In previous research, we have established that the major digestive peptidase of an insect -cathepsin L-hydrolyzes immunogenic prolamins after Gln residues but is unstable in the extremely acidic environment (pH 2-4) of the human stomach and cannot be used as a digestive aid. In this work, using molecular dynamics simulations, we discover the probable cause of the pH instability of cathepsin L-loss of the catalytically competent rotameric state of one of the active site residues, His 275. To "fix" the correct orientation of this residue, we designed a V277A mutant variant, which extends the range of stability of the peptidase in the acidic environment while retaining most of its activity. We suggest this protein as a lead glutenase for the development of oral medical preparation that fights CD and gluten intolerance in susceptible people.
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ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms241512369