Rational Design of an Oral Enzyme Therapeutic: A Novel Approach for Celiac Disease

Rational design of proteins seeks to develop enzymes with particular function by engineering the protein’s structure. This is an exceedingly difficult task since the tools are often indirect. Plus, structure obtained from a solid protein crystal may not correlate with solution structure and activity. However, a group at the University of Washington (Seattle) reports doing just that to engineer a synthetic enzyme to metabolize in vivo the immunogenic peptides responsible for celiac disease.1

Celiac disease is an inflammatory reaction in the human digestive tract triggered by α-gliadin, which is a component of gluten. Gluten-free foods are devoid of wheat, barley, or rye. α-Gliadin in these grains resists complete digestion of oligopeptides with high proline and glutamine content (P-Q). The oligopeptides trigger a severe autoimmune response in celiac patients.

Gordon et al.1 set out to develop an oral enzyme therapeutic (OET) with the following properties: 1) active for digestion of proline-glutamine rich oligopeptides in stomach acid environment, 2) inert to common digestive proteases, and 3) compatible with recombinant production.

They selected an endopeptidase (kumamolism-As) since it is active at low pH. The Rosetta Molecular Modeling Suite was used to identify mutations expected to improve oligiopeptide specificity. The activity of the resulting enzyme was 116× the native form and 887 times faster for P-Q oligopeptides. A firm has been founded to commercialize this invention (Proteus Biologics, founded by Ingrid Pultz, Justin Siegel, and David Baker, who are among the authors in Ref. 1).

Congratulations to the team! The paper reads like a chronicle of building the Panama Canal or the Golden Gate Bridge. The story is compelling and worth mentioning to nontechnical colleagues. It will be interesting to see if this approach is superior to “gluten-free” food products, which are so popular, especially among the health food and nutraceutical set.

Reference

  1. Gordon, S.R. et al. Computational design of an α-gliadin peptidase. J. Am. Chem. Soc. 2012, 134, 20513−20.

Robert L. Stevenson, Ph.D., is a Consultant and Editor of Separation Science for American Laboratory/Labcompare; e-mail: rlsteven@yahoo.com.

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