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Lookup NU author(s): Professor Mike ProbertORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.We report the design, synthesis, and characterization of a novel class of all-peptide macrocycles, Cyclo-Polyprolines (CP). Exploiting the precision of Fmoc-based solid-phase peptide synthesis (SPPS) and head-to-tail macrocyclization, this platform grants unparalleled control over the macrocycle's primary sequence and secondary structure, offering a viable route toward exo-/endo-functionalization and addressing a bottleneck of traditional synthetic host macrocycles. The resulting CP scaffold is highly amphiphilic, exhibiting excellent solubility in both organic and aqueous media. Structural analysis via NMR spectroscopy and single-crystal x-ray diffraction reveals a distinct chameleonic character: the macrocycle shifts from an all-junctions-cis conformation in organic solvents to a predominantly all-junctions-trans isomer in water. We demonstrate that this transition is driven by a cooperative hydration effect, wherein water molecules stabilize the expanded framework through precise two-point hydrogen bonding. Demonstrating responsive host-guest capabilities, CP undergoes induced-fit isomerization to bind ligands, successfully forming, among other species, an all-peptide pseudo-rotaxane. This methodology establishes a robust platform for creating functionalized, proline-based hosts with significant potential in medicinal chemistry, drug delivery, and organocatalysis, thereby bridging the gap between supramolecular systems and enzyme mimetics.
Author(s): Girolamo CD, Fleming PC, Kwawu CR, Guimaraes AR, Muldoon J, Bruno-Colmenarez J, Ortin Y, Probert MR, Fantuzzi F, Palma A
Publication type: Article
Publication status: Published
Journal: Angewandte Chemie - International Edition
Year: 2026
Pages: epub ahead of print
Online publication date: 14/05/2026
Acceptance date: 30/04/2026
Date deposited: 01/06/2026
ISSN (print): 1433-7851
ISSN (electronic): 1521-3773
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/anie.8698780
DOI: 10.1002/anie.8698780
Data Access Statement: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions
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