title: Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients.
abstract: Enhancing the oral bioavailability of peptide drug leads is a major challenge in drug design. As such, methods to address this challenge are highly sought after by the pharmaceutical industry. Here, we propose a strategy to identify appropriate amides for N-methylation using temperature coefficients measured by NMR to identify exposed amides in cyclic peptides. N-methylation effectively caps these amides, modifying the overall solvation properties of the peptides and making them more membrane permeable. The approach for identifying sites for N-methylation is a rapid alternative to the elucidation of 3D structures of peptide drug leads, which has been a commonly used structure-guided approach in the past. Five leucine-rich peptide scaffolds are reported with selectively designed N-methylated derivatives. In vitro membrane permeability was assessed by parallel artificial membrane permeability assay and Caco-2 assay. The most promising N-methylated peptide was then tested in vivo. Here we report a novel peptide (15), which displayed an oral bioavailability of 33% in a rat model, thus validating the design approach. We show that this approach can also be used to explain the notable increase in oral bioavailability of a somatostatin analog.
authors.forename: Conan K
authors.initials: CK
authors.lastname: Wang
authors.forename: Susan E
authors.initials: SE
authors.lastname: Northfield
authors.forename: Barbara
authors.initials: B
authors.lastname: Colless
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chaousis
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hamernig
authors.forename: Rink-Jan
authors.initials: RJ
authors.lastname: Lohman
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Nielsen
authors.forename: Christina I
authors.initials: CI
authors.lastname: Schroeder
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000737:chemistry*; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002853:Chromatography, Liquid; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008745:Methylation; D010455:Peptides / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010539:Permeability; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D051381:Rats; D017208:Rats, Wistar; D012997:Solvents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature
chemical_list: D000577:Amides; D010455:Peptides; D012997:Solvents