title: Cyclic Penta- and Hexaleucine Peptides without N-Methylation Are Orally Absorbed.
abstract: Development of peptide-based drugs has been severely limited by lack of oral bioavailability with less than a handful of peptides being truly orally bioavailable, mainly cyclic peptides with N-methyl amino acids and few hydrogen bond donors. Here we report that cyclic penta- and hexa-leucine peptides, with no N-methylation and five or six amide NH protons, exhibit some degree of oral bioavailability (4-17%) approaching that of the heavily N-methylated drug cyclosporine (22%) under the same conditions. These simple cyclic peptides demonstrate that oral bioavailability is achievable for peptides that fall outside of rule-of-five guidelines without the need for N-methylation or modified amino acids.
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hill
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Rink-Jan
authors.initials: RJ
authors.lastname: Lohman
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Huy N
authors.initials: HN
authors.lastname: Hoang
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Nielsen
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Conor C G
authors.initials: CC
authors.lastname: Scully
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: W Mei
authors.initials: WM
authors.lastname: Kok
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Ligong
authors.initials: L
authors.lastname: Liu
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lucke
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Stoermer
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Christina I
authors.initials: CI
authors.lastname: Schroeder
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chaousis
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Colless
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland , Brisbane 4072, Australia.
authors.forename: Paul V
authors.initials: PV
authors.lastname: Bernhardt
authors.affiliation: World Wide Medicinal Chemistry, CVMED, Pfizer , Cambridge, Massachusetts 02140, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Edmonds
authors.affiliation: World Wide Medicinal Chemistry, CVMED, Pfizer , Cambridge, Massachusetts 02140, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith
authors.affiliation: Pfizer Pharmacokinetics, Dynamics, and Metabolism , Groton, Connecticut 06340, United States.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Rotter
authors.affiliation: World Wide Medicinal Chemistry, CVMED, Pfizer , Cambridge, Massachusetts 02140, United States.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Ruggeri
authors.affiliation: World Wide Medicinal Chemistry, CVMED, Pfizer , Cambridge, Massachusetts 02140, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: World Wide Medicinal Chemistry, CVMED, Pfizer , Cambridge, Massachusetts 02140, United States.
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
keywords: Oral bioavailability; absorption; peptides; permeability; rule of five