Highly Conformationally Restricted Cyclopropane Tethers with Three‐Dimensional Structural Diversity Drastically Enhance the Cell Permeability of Cyclic Peptides

• Published in: Chemistry : a European journal 2017-03, Vol.23 (13), p.3034-3041
• Main Authors: Matsui, Kouhei, Kido, Yasuto, Watari, Ryosuke, Kashima, Yousuke, Yoshida, Yutaka, Shuto, Satoshi
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Biological properties; Cell Line; Cell Membrane Permeability; cell permeability; Chemistry; conformation analysis; cyclic peptides; Cyclopropane; Cyclopropanes - chemical synthesis; Cyclopropanes - chemistry; Cyclopropanes - pharmacokinetics; Magnetic Resonance Spectroscopy; Methylation; Models, Molecular; Molecular Conformation; NMR spectroscopy; Peptides; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacokinetics; Permeability; Protein Structure, Secondary; Strategy; Swine; Tethers; Three dimensional models
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201604946

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. Conformation analysis: A new strategy that can dramatically change the conformation and physicochemical properties of cyclic peptides having an all l‐amino acid sequence by introducing only a cyclopropane tether (CPT) is presented. Particularly, the introduction of a cis‐NfCf fixed a conformation suitable for passive transport and substantially improved the cell permeability of the model cyclic peptide (see scheme).