title: Highly Conformationally Restricted Cyclopropane Tethers with Three-Dimensional Structural Diversity Drastically Enhance the Cell Permeability of Cyclic Peptides.
abstract: The conformation of cyclic peptides is closely related to their physicochemical and biological properties, but their rational design to obtain a conformation with the desired properties is difficult. Herein, we present a new strategy by using conformationally restricted cyclopropane tethers (CPTs) to control the conformation and improve the cell permeability of cyclic peptides regardless of the amino acid sequence. Newly designed cis- or trans-CPTs with three-dimensional structural diversity were introduced into a model cyclic peptide, and the relationship between the conformation of the cyclic peptides and their cell permeability was analyzed. Peptides containing a CPT exhibited conformational diversity due to the characteristic steric feature of cyclopropane, among which peptides containing a CPT, cis-NfCf had remarkably higher cell permeability than peptides containing other CPTs-even superior to that of cyclosporine A, a known permeable cyclic peptide.
authors.affiliation: Pharmaceutical Research Center, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka-shi, Osaka, 561-0825, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Matsui
authors.affiliation: Pharmaceutical Research Center, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka-shi, Osaka, 561-0825, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Kido
authors.affiliation: Pharmaceutical Research Center, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka-shi, Osaka, 561-0825, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Watari
authors.affiliation: Pharmaceutical Research Center, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka-shi, Osaka, 561-0825, Japan.
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Kashima
authors.affiliation: Pharmaceutical Research Center, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka-shi, Osaka, 561-0825, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
authors.forename: Satoshi
authors.identifier: http://orcid.org/0000-0001-7850-8064
authors.initials: S
authors.lastname: Shuto
mesh_terms: D000818:Animals; D002460:Cell Line; D002463:Cell Membrane Permeability; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D008958:Models, Molecular; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D017433:Protein Structure, Secondary; D013552:Swine
chemical_list: D003521:Cyclopropanes; D010456:Peptides, Cyclic; C030797:cyclopropane
keywords: NMR spectroscopy; cell permeability; conformation analysis; cyclic peptides; cyclopropane