Highly Conformationally Restricted Cyclopropane Tethers with Three‐Dimensional Structural Diversity Drastically Enhance the Cell Permeability of Cyclic Peptides. Issue 13 (27th December 2016)

• Record Type: Journal Article
• Authors: Matsui, Kouhei; Kido, Yasuto; Watari, Ryosuke; Kashima, Yousuke; Yoshida, Yutaka; Shuto, Satoshi
• Is Part Of: Chemistry. Volume 23:Issue 13(2017)
• Page Start: 3034
• Page End: 3041
• Publication Date: 2016-12-27
• Subjects: cell permeability -- conformation analysis -- cyclic peptides -- cyclopropane -- NMR spectroscopy; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201604946
• Languages: English
• ISSNs: 0947-6539

Abstract

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. Abstract : Conformation analysis : A new strategy that can dramatically change the conformation and physicochemical properties of cyclic peptides having an alll ‐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).