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J Pharmacol Exp Ther. 2004 May 13 [Epub ahead of print]

EFFECT OF PROLYL ENDOPEPTIDASE ON DIGESTIVE-RESISTANT GLIADIN PEPTIDES IN
VIVO.

Piper JL, Gray GM, Khosla C.

Stanford University.

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 alpha-
and gamma-gliadin peptides believed to induce toxicity via diverse
mechanisms. Most were highly resistant to gastric and pancreatic protease
digestion, but 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 co-
perfused into rat intestine with the highly digestive resistant 33-mer
peptide, LQLQPF(PQPQLPY)3PQPQPF, (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 co-perfusion
with a mixture of 33-mer and partially proteolyzed gliadin. This data
verifies and extends our earlier proposal that gliadin peptides, while
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.

PMID: 15143130 [PubMed - as supplied by publisher]

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