Current status of rational design of prodrugs targeting the intestinal di/tri-peptide transporter hPEPT1 (SLC15A1)

The intestinal di/tri-peptide transporter hPEPT1 has broad substrate specificity, accommodating uptake of the majority of investigated di- and tripeptides, as well as of a number of drug compounds. This transport system has a high capacity and it has been hypothesized that hPEPT1-mediated uptake of drug compounds, conjugated with promoieties so as to resemble di- or tripeptides, may be a strategy for increasing the intestinal permeability of compounds with otherwise low bioavailability. Based on the research activities of our group during the last decade, as well as on general research in the field, the present review aims at giving a brief overview of structure-activity relationships for hPEPT1, and to provide a critical evaluation of whether hPEPT1-targeted prodrugs can be rationally designed.