cis-Peptide Bonds: A Key for Intestinal Permeability of Peptides? .
Recent structural studies on libraries of cyclic hexapeptides led to the identification of common backbone conformations that may be instrumental to the oral availability of peptides. Furthermore, the observation of differential Caco-2 permeabilities of enantiomeric pairs of some of these peptides strongly supports the concept of conformational specificity driven uptake and also suggests a pivotal role of carrier-mediated pathways for peptide transport, especially for scaffolds of polar nature. This work presents investigations on the Caco-2 and PAMPA permeability profiles of 13 selected N-methylated cyclic pentaalanine peptides derived from the basic cyclo(-D-Ala-Ala4 -) template. These molecules generally showed moderate to low transport in intestinal epithelia with a few of them exhibiting a Caco-2 permeability equal to or slightly higher than that of mannitol, a marker for paracellular permeability. We identified that the majority of the permeable cyclic penta- and hexapeptides possess an N-methylated cis-peptide bond, a structural feature that is also present in the orally available peptides cyclosporine A and the tri-N-methylated analogue of the Veber-Hirschmann peptide. Based on these observations it appears that the presence of N-methylated cis-peptide bonds at certain locations may promote the intestinal permeability of peptides through a suitable conformational preorganization.
Institute for Advanced Study (IAS) and, Center for Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München, 85747 Garching (Germany).
Udaya Kiran
UK
Marelli
Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120 (Israel).
Oded
O
Ovadia
Institute for Advanced Study (IAS) and, Center for Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München, 85747 Garching (Germany).|Present address: Novartis Institutes for BioMedical Research (NIBR), Global Discovery Chemistry, Emeryville, CA 94608 (USA).
Andreas Oliver
AO
Frank
Institute for Advanced Study (IAS) and, Center for Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München, 85747 Garching (Germany).
Jayanta
J
Chatterjee
Institute of Chemistry, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem, 91904 (Israel).
Chaim
C
Gilon
Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120 (Israel).
Amnon
A
Hoffman
Institute for Advanced Study (IAS) and, Center for Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München, 85747 Garching (Germany). kessler@tum.de.
Horst
H
Kessler
D001692:Biological Transport; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000737:chemistry*; D008745:Methylation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D010539:Permeability; D013237:Stereoisomerism
D010455:Peptides; D010456:Peptides, Cyclic
cis-peptide bond; conformation; drug design; oral availability; peptides