We described new synthetic routes for (Z)-alkene or (E)-fluoroalkene dipeptide isosteres as cis-amide equivalents and application of the synthetic dipeptide isosteres to probe structural requirement of peptide transporter (PEPT1). We evaluated affinities of synthetic Phe-Gly derivatives for human di/tripeptide transporter, PEPT1. In this experiment, trans-amide isosteres exhibited superior affinities for PEPT1 compared to cis-amide equivalents. This result suggested that PEPT1 predominantly recognizes trans-amide conformations of dipeptides.
