title: Going Out on a Limb: Delineating The Effects of β-Branching, N-Methylation, and Side Chain Size on the Passive Permeability, Solubility, and Flexibility of Sanguinamide A Analogues.
abstract: It is well established that intramolecular hydrogen bonding and N-methylation play important roles in the passive permeability of cyclic peptides, but other structural features have been explored less intensively. Recent studies on the oral bioavailability of the cyclic heptapeptide sanguinamide A have raised the question of whether steric occlusion of polar groups via β-branching is an effective, yet untapped, tool in cyclic peptide permeability optimization. We report the structures of 17 sanguinamide A analogues designed to test the relative contributions of β-branching, N-methylation, and side chain size to passive membrane permeability and aqueous solubility. We demonstrate that β-branching has little effect on permeability compared to the effects of aliphatic carbon count and N-methylation of exposed NH groups. We highlight a new N-methylated analogue of sanguinamide A with a Leu substitution at position 2 that exhibits solvent-dependent flexibility and improved permeability over that of the natural product.
authors: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors: Andrew T
authors: AT
authors: Bockus
authors: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors: Joshua A
authors: JA
authors: Schwochert
authors: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors: Cameron R
authors: CR
authors: Pye
authors: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors: Chad E
authors: CE
authors: Townsend
authors: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors: Vong
authors: V
authors: Sok
authors: Department of Antibody Discovery & Protein Engineering, Medimmune Ltd , Cambridge CB21 6GH, United Kingdom.
authors: Maria A
authors: MA
authors: Bednarek
authors: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors: R Scott
authors: RS
authors: Lokey
mesh_terms: D018938:Caco-2 Cells; D006801:Humans; D008567:Membranes, Artificial; D008745:Methylation; D056004:Molecular Dynamics Simulation; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism; D010539:Permeability; D012995:Solubility; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism; D014867:Water
chemical_list: D008567:Membranes, Artificial; D010456:Peptides, Cyclic; D013844:Thiazoles; C579658:sanguinamide A; D014867:Water