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Updated: Mar 11, 2026

Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
Published on: September 19, 2022
Highly Conformationally Restricted Cyclopropane Tethers with Three-Dimensional Structural Diversity Drastically
Kouhei Matsui1, Yasuto Kido1, Ryosuke Watari1
1Pharmaceutical Research Center, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka-shi, Osaka, 561-0825, Japan.
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.
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