An endogenous solute uptake pathway for oral peptide delivery

The intestinal epithelium restricts causal uptake of luminal contents to maintain homeostasis. We have identified nutrient-driven mechanism that transiently increase intestinal paracellular permeability properties and used this information to rationally design two stable Permeant Inhibitor of Phosphatase (PIP) peptides that dynamically increase the phosphorylation state of intracellular epithelial myosin light chain (MLC) phosphorylation. Apical application of PIP peptides resulted in a reversible and non-toxic transient reduction in Caco-2 monolayer trans-epithelial electric resistance and enhanced paracellular flux in vitro. Direct injection of PIP peptides with human insulin into the lumen of rat jejunum decrease blood glucose levels that was PIP peptide- and insulin dose-dependent and correlated with increased pMLC levels. Together, these studies add validation to the presence of an endogenous mechanism involving pMLC used by the intestinal epithelium to dynamically regulate its paracellular permeability properties and provide a potential means to enhance the oral uptake of peptide therapeutics via a defined mechanism of action.