title: Improving on nature: making a cyclic heptapeptide orally bioavailable.
abstract: The use of peptides in medicine is limited by low membrane permeability, metabolic instability, high clearance, and negligible oral bioavailability. The prediction of oral bioavailability of drugs relies on physicochemical properties that favor passive permeability and oxidative metabolic stability, but these may not be useful for peptides. Here we investigate effects of heterocyclic constraints, intramolecular hydrogen bonds, and side chains on the oral bioavailability of cyclic heptapeptides. NMR-derived structures, amide H-D exchange rates, and temperature-dependent chemical shifts showed that the combination of rigidification, stronger hydrogen bonds, and solvent shielding by branched side chains enhances the oral bioavailability of cyclic heptapeptides in rats without the need for N-methylation.
authors.affiliation: Division of Chemistry and Structural Biology, University of Qld, Brisbane, Qld 4072 (Australia).
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Nielsen
authors.forename: Huy N
authors.initials: HN
authors.lastname: Hoang
authors.forename: Rink-Jan
authors.initials: RJ
authors.lastname: Lohman
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hill
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lucke
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
authors.forename: David J
authors.initials: DJ
authors.lastname: Edmonds
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Rotter
authors.forename: Roger B
authors.initials: RB
authors.lastname: Ruggeri
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D001682:Biological Availability; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011487:Protein Conformation
chemical_list: D009842:Oligopeptides; D010456:Peptides, Cyclic
keywords: NMR; cyclic peptides; oral bioavailability; permeability