title: Effect of structural and conformation modifications, including backbone cyclization, of hydrophilic hexapeptides on their intestinal permeability and enzymatic stability.
abstract: A library of 18 hexapeptide analogs was synthesized, including sub-libraries of N- or C-methylation of the parent hexapeptide Phe-Gly-Gly-Gly-Gly-Phe, as well as backbone cyclized analogs of each linear analog with various ring sizes. N- or C-methylation as well as cyclization (but not backbone cyclization) have been suggested to improve intestinal permeability and metabolic stability of peptides in general. Here we aimed to assess their applicability to hydrophilic peptides. The intestinal permeability (Papp) of the 18-peptide library was in the range of 0.2-6.8 x 10-6 cm/sec. Based on several tests, we concluded that the absorption mechanism of all tested analogs is paracellular, regardless of the structural or conformational modifications. In all cases, backbone cyclization increased Papp (5-fold) in comparison to the linear analogs due to the smaller 3D size and also dramatically decreased peptide proteolysis by brush border enzymes. N- or C-methylation did not enhance the permeability of the linear analogs in this series.
authors.affiliation: Departments of Pharmaceutics and Organic Chemistry, and the Wolfson Centre for Applied Structural Biology, The Hebrew University of Jerusalem, Safra Campus, Jerusalem 91904, Israel.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Hess
authors.forename: Oded
authors.initials: O
authors.lastname: Ovadia
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Shalev
authors.forename: Hanoch
authors.initials: H
authors.lastname: Senderovich
authors.forename: Bashir
authors.initials: B
authors.lastname: Qadri
authors.forename: Tamar
authors.initials: T
authors.lastname: Yehezkel
authors.forename: Yoseph
authors.initials: Y
authors.lastname: Salitra
authors.forename: Tania
authors.initials: T
authors.lastname: Sheynis
authors.forename: Raz
authors.initials: R
authors.lastname: Jelinek
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D003500:Cyclization; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008353:Mannitol / Q000493:pharmacokinetics; D008745:Methylation; D008871:Microvilli / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D008081:Liposomes; D009842:Oligopeptides; D010456:Peptides, Cyclic; D008353:Mannitol