Enzymatic barriers for GI peptide and protein delivery.

The oral delivery of therapeutic peptides and proteins is a major challenge to pharmaceutical science. The gastrointestinal (GI) tract contains many endo- and exopeptidases, enzymes that hydrolyze peptide bonds and act synergistically to degrade proteins and peptides. It is important to have both qualitative and quantitative data on these peptidases when devising strategies for oral peptide and protein delivery. The greatest threat to therapeutic peptides lies in the lumen of the small intestine, which contains gram quantities of peptidases secreted from the pancreas, as well as cellular peptidases from the mucosal cells, which are constantly sloughed off from the villi. The second major enzymatic barrier is the brush border membrane of the epithelial cells, which contains at least 15 peptidases that together have a broad specificity and can degrade both proteins and peptides. Lysosomal peptidases will also present a barrier to any peptides or proteins endocytosed by the epithelial cells. Although the colon has received some attention as a possible site for peptide delivery, evidence shows that the lumen of the colon contains substantial amounts of peptidase activity, largely because of enzyme production by microorganisms. From a knowledge of the enzymatic barrier, the strategies for oral peptide delivery of enzyme inhibition and the synthesis of enzyme-resistant peptide analogues are logical developments. The latter approach is the most promising.