TY - JOUR T1 - Effect of Prolyl Endopeptidase on Digestive-Resistant Gliadin Peptides in Vivo JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 213 LP - 219 DO - 10.1124/jpet.104.068429 VL - 311 IS - 1 AU - Justin L. Piper AU - Gary M. Gray AU - Chaitan Khosla Y1 - 2004/10/01 UR - http://jpet.aspetjournals.org/content/311/1/213.abstract N2 - Many gluten peptides elicit proliferative responses from T cells from Celiac Sprue patients, influencing the pathogenesis of this small intestinal disorder. These peptides are Pro- and Gln-rich in character, suggesting that resistance to proteolysis promotes their toxicity. To test this hypothesis, we analyzed the digestive resistance of a panel of α- and γ-gliadin peptides believed to induce toxicity via diverse mechanisms. Most were highly resistant to gastric and pancreatic protease digestion, but they were digested by intestinal brush-border peptidases. In some instances, there was accumulation of relatively long intermediates. Control peptides from gliadin and myoglobin revealed that digestive resistance depended on factors other than size. Prolyl endopeptidase (PEP) supplementation substantially reduced the concentrations of these peptides. To estimate a pharmacologically useful PEP dose, recombinant PEP was coperfused into rat intestine with the highly digestive-resistant 33-mer peptide LQLQPF(PQPQLPY)3 PQPQPF (PEP: peptide weight ratio 1:50 to 1:5). PEP dosing experiments indicate significant changes in the average residence time. The in vivo benefit of PEP was verified by coperfusion with a mixture of 33-mer and partially proteolyzed gliadin. These data verify and extend our earlier proposal that gliadin peptides, although resistant to proteolysis, can be processed efficiently by PEP supplementation. Indeed, PEP may be able to treat Celiac Sprue by reducing or eliminating such peptides from the intestine. The American Society for Pharmacology and Experimental Therapeutics ER -