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


ABSTRACT: 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 Tribolium castaneum-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.

SUBMITTER: Chugunov AO 

PROVIDER: S-EPMC10418366 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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

Chugunov Anton O AO   Dvoryakova Elena A EA   Dyuzheva Maria A MA   Simonyan Tatyana R TR   Tereshchenkova Valeria F VF   Filippova Irina Yu IY   Efremov Roman G RG   Elpidina Elena N EN  

International journal of molecular sciences 20230802 15


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 gli  ...[more]

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