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Abstract

In order to study the influence of hydrogen bonding in the amide backbone of a peptide on permeability across a cell membrane, a series of tetrapeptide analogues was prepared from D-phenylalanine. The amide nitrogens in the parent oligomer were sequentially methylated to give a series containing from one to four methyl groups. The transport of these peptides was examined across confluent monolayers of Caco-2 cells as a model of the intestinal mucosa. The results of these studies showed a substantial increase in transport with each methyl group added. Only slight difference in the octanol-water partition coefficient accompanied this alkylation, suggesting that the increase in permeability is not due to lipophilicity considerations. These observations are, however, consistent with a model in which hydrogen bonding in the backbone is a principal determinant of transport. Methylation is seen to reduce the overall hydrogen bond potential of the peptide and increases flux by this mechanism. These results suggest that alkylation of the amides in the peptide chain is an effective way to improve the passive absorption potential for this class of compounds.

Correlation of Drug Absorption with Molecular Surface Properties

“…26,27 Recently the potential capacity to form intermolecular hydrogen bonds with water has been reintroduced as a predictor of drug and peptide absorption. 28,29 Interestingly, pindolol, metoprolol, and oxprenolol, which have the same potential hydrogen bond formation capacity, had significantly different permeability coefficients, indicating that the theoretical calculation of hydrogen-bonding capacity is not applicable on the -receptor antagonists. This is probably because this simple method does not consider the three-dimensional shape of the molecule.…”

In Silico Prediction of Drug Permeability Across Buccal Mucosa

“…The reason for the importance of HBD in permeability might be the predominant presence of hydrogen bond acceptors in the head group regions of membrane bilayer lipids (11). As a result, the permeability of solutes with significant hydrogen bonding donor tendencies is restricted (41,42). The presence of nRotB in the model indicated that a greater flexibility of a molecule favors buccal permeation.…”

Mechanistic Roles of Neutral Surfactants on Concurrent Polarized and Passive Membrane Transport of a Model Peptide in Caco-2 Cells

“…Samples (100 µL) were then withdrawn carefully from the AP side and replaced with the same volume of fresh surfactant solution. Previous studies with this peptide showed it to be stable in the presence of Caco-2 cells; 19 therefore the amount of radioactive peptide transported was determined in a Beckman LS 6000 IC liquid scintillation counter.…”