Epithelial cell permeability of a series of peptidic HIV protease inhibitors: Aminoterminal substituent effects

The influence of the aminoterminal substituent in a homologous series of tetrapeptide analogs on transport across Caco-2 cell monolayers was studied. In a series of pyridylcarboxamide regioisomers, the 2-pyridyl isomer was significantly more permeable than either the 3- or 4-congeners. The uniqueness of this peptide was further suggested by examining the partitioning behavior between heptane and ethylene glycol, a system which has been developed as a simple estimate of the desolvation energy or hydrogen bonding potential of a peptide. In this model, the 2-isomer has a much larger partition coefficient than either the 3- or 4-analogs, consistent with its being less solvated than expected based on simple structural considerations. Factors possibly contributing to this decreased effective polarity could be steric interactions or intramolecular hydrogen bonding.