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

Abstract

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.

Key Words:

• Peptide
• desolvation
• hydrogen bonding
• partition coefficient