Dual Action of the PN159/KLAL/MAP Peptide: Increase of Drug Penetration across Caco-2 Intestinal Barrier Model by Modulation of Tight Junctions and Plasma Membrane Permeability
Alexandra Bocsik,
Ilona Gróf,
Lóránd Kiss,
Ferenc Ötvös,
Ottó Zsíros,
Lejla Daruka,
Lívia Fülöp,
Monika Vastag,
Ágnes Kittel,
Norbert Imre,
Tamás A. Martinek,
Csaba Pál,
Piroska Szabó-Révész,
Mária A. Deli
Affiliations
Alexandra Bocsik
Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary
Ilona Gróf
Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary
Lóránd Kiss
Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary
Ferenc Ötvös
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary
Ottó Zsíros
Plant Biology, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary
Lejla Daruka
Doctoral School in Biology, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, Hungary
Lívia Fülöp
Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Hungary
Monika Vastag
Division of Pharmacology and Drug Safety Research, Gedeon Richter Plc., H-1103 Budapest, Hungary
Ágnes Kittel
Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1450 Budapest, Hungary
Norbert Imre
Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Hungary
Tamás A. Martinek
Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Hungary
Csaba Pál
Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary
Piroska Szabó-Révész
Department of Pharmaceutical Technology, University of Szeged, H-6720 Szeged, Hungary
Mária A. Deli
Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary
The absorption of drugs is limited by the epithelial barriers of the gastrointestinal tract. One of the strategies to improve drug delivery is the modulation of barrier function by the targeted opening of epithelial tight junctions. In our previous study the 18-mer amphiphilic PN159 peptide was found to be an effective tight junction modulator on intestinal epithelial and blood⁻brain barrier models. PN159, also known as KLAL or MAP, was described to interact with biological membranes as a cell-penetrating peptide. In the present work we demonstrated that the PN159 peptide as a penetration enhancer has a dual action on intestinal epithelial cells. The peptide safely and reversibly enhanced the permeability of Caco-2 monolayers by opening the intercellular junctions. The penetration of dextran molecules with different size and four efflux pump substrate drugs was increased several folds. We identified claudin-4 and -7 junctional proteins by docking studies as potential binding partners and targets of PN159 in the opening of the paracellular pathway. In addition to the tight junction modulator action, the peptide showed cell membrane permeabilizing and antimicrobial effects. This dual action is not general for cell-penetrating peptides (CPPs), since the other three CPPs tested did not show barrier opening effects.
