title: In vitro characterization of human peptide transporter hPEPT1 interactions and passive permeation studies of short cationic antimicrobial peptides.
abstract: The present study assesses the permeation of cationic antimicrobial di- and tripeptides derived from lactoferricin via interaction with the human intestinal peptide transporter hPEPT1 and via passive routes. While some tested peptides displayed moderate affinity (0.6 and 2.7 mM) for interaction with hPEPT1, none served as substrate for hPEPT1 expressed by Xenopus laevis oocytes. It is shown that structural strategies employed to generate sufficient biological activity and metabolic stability such as introduction of large hydrophobic unnatural amino acids and different C-terminal modifications counteracted hPEPT1 mediated uptake. Most of the included peptides were nevertheless shown to permeate at rates suggesting moderate to excellent human oral absorption in the applied phospholipid vesicle-based passive permeation assay. Although the main factor governing passive permeation appears to be the hydrophobicity, peptide structure was also important and the overall permeation behavior was difficult to predict. Comparisons with a theoretical prediction model were also performed.
authors.affiliation: Department of Pharmacy, University of Tromsø, N-9037, Tromsø, Norway.
authors.forename: Gøril Eide
authors.initials: GE
authors.lastname: Flaten
authors.forename: Gabor
authors.initials: G
authors.lastname: Kottra
authors.forename: Wenche
authors.initials: W
authors.lastname: Stensen
authors.forename: Geir
authors.initials: G
authors.lastname: Isaksen
authors.forename: Rasmus
authors.initials: R
authors.lastname: Karstad
authors.forename: John S
authors.initials: JS
authors.lastname: Svendsen
authors.forename: Hannelore
authors.initials: H
authors.lastname: Daniel
authors.forename: Johan
authors.initials: J
authors.lastname: Svenson
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D000074011:Peptide Transporter 1; D010539:Permeability; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding; D027981:Symporters / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; D000074011:Peptide Transporter 1; D010743:Phospholipids; D027981:Symporters