The Influence of Peptide Structure on Transport Across Caco-2 Cells

The relationship between structure and permeability of peptides across epithelial cells was studied. Using confluent monolayers of Caco-2 cells as a model of the intestinal epithelium, permeability coefficients were obtained from the steady-state flux of a series of neutral and zwitterionic peptides prepared from D-phenylalanine and glycine. Although these peptides ranged in lipophilicity (log octanol/water partition coefficient) from −2.2 to +2.8, no correlation was found between the observed flux and the apparent lipophilicity. However, a strong correlation was found for the flux of the neutral series and the total number of hydrogen bonds the peptide could potentially make with water. These results suggest that a major impediment to peptide passive absorption is the energy required to break water–peptide hydrogen bonds in order for the solute to enter the cell membrane. This energy appears not to be offset by the favorable introduction of lipophilic side chains in the amino acid residues.

[1]  M A Roseman,et al.  Hydrophobicity of the peptide C=O...H-N hydrogen-bonded group. , 1988, Journal of molecular biology.

[2]  Thomas J. Raub,et al.  Biophysical model approaches to mechanistic transepithelial studies of peptides , 1990 .

[3]  J. Madara,et al.  Loosening tight junctions. Lessons from the intestine. , 1989, The Journal of clinical investigation.

[4]  W. Higuchi,et al.  Advancing quantitative and mechanistic approaches in interfacing gastrointestinal drug absorption studies in animals and humans , 1983 .

[5]  M A Roseman,et al.  Hydrophilicity of polar amino acid side-chains is markedly reduced by flanking peptide bonds. , 1988, Journal of molecular biology.

[6]  E. M. Renkin,et al.  FILTRATION, DIFFUSION, AND MOLECULAR SIEVING THROUGH POROUS CELLULOSE MEMBRANES , 1954, The Journal of general physiology.

[7]  J. Diamond,et al.  Molecular forces governing non-electrolyte permeation through cell membranes , 1969, Proceedings of the Royal Society of London. Series B. Biological Sciences.

[8]  J. Dietschy,et al.  Delineation of the dimensions and permeability characteristics of the two major diffusion barriers to passive mucosal uptake in the rabbit intestine. , 1974, The Journal of clinical investigation.

[9]  Thomas J. Raub,et al.  Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. , 1989, Gastroenterology.

[10]  R. Conradi,et al.  Caco-2 Cell Monolayers as a Model for Drug Transport Across the Intestinal Mucosa , 1990, Pharmaceutical Research.

[11]  Yehuda Katz,et al.  Interpretation of nonelectrolyte partition coefficients between dimyristoyl lecithin and water , 2005, The Journal of Membrane Biology.

[12]  G. Rose,et al.  Hydrophobicity of amino acid residues in globular proteins. , 1985, Science.

[13]  N. Lakshminarayanaiah.  Equations of membrane biophysics , 1984 .

[14]  P. Artursson,et al.  Transport and permeability properties of human Caco-2 cells: An in vitro model of the intestinal epithelial cell barrier , 1990 .

[15]  R Griffiths,et al.  Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists. , 1988, Journal of medicinal chemistry.

[16]  E. Benedetti,et al.  Restricted rotation in amides—VI : Configurations and conformations of unsymmetrical tertiary benzamides , 1975 .

[17]  I. M. Klotz,et al.  Stability of an amide-hydrogen bond in an apolar environment. , 1968, Biochemistry.