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Lookup NU author(s): Dr Tom McAllisterORCiD, Professor Akane Kawamura
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH. CD59 is an immunomodulatory cell surface receptor associated with human disease. Despite its importance in complement regulation and bacterial pathogenesis, CD59 remains a challenging therapeutic target. Research to date has focused on antibody or protein-based strategies. Here we present a new approach to target CD59 using macrocyclic peptides with low nanomolar affinity for CD59. Through X-ray crystallographic studies and structure-activity relationship (SAR) studies, we identify key interactions that are essential for binding and activity. We find that the macrocyclic peptide CP-06 adopts a beta-hairpin structure and binds CD59 through an intermolecular beta-sheet, mimicking protein–protein interactions of biologically relevant CD59 interaction partners. We create dimeric and lipidated macrocyclic peptide conjugates as enhanced cell-active CD59 inhibitors and show that these probes can be used to modulate both complement-mediated killing of human cells and lytic activity of bacterial virulence factors. Together, our data provide a starting point for future development of macrocyclic peptides to target CD59 activity in diverse cellular contexts.
Author(s): Bickel JK, Ahmed AIS, Pidd AB, Morgan RM, McAllister TE, Horrell S, Couves EC, Nagaraj H, Bartlett EJ, El Omari K, Kawamura A, Bubeck D, Tate EW
Publication type: Article
Publication status: Published
Journal: Angewandte Chemie - International Edition
Year: 2025
Pages: Epub ahead of print
Online publication date: 24/04/2025
Acceptance date: 23/04/2025
Date deposited: 13/05/2025
ISSN (print): 1433-7851
ISSN (electronic): 1521-3773
Publisher: John Wiley and Sons Inc.
URL: https://doi.org/10.1002/anie.202422673
DOI: 10.1002/anie.202422673
Data Access Statement: The data that support the findings of this study are available in the supplementary material of this article.
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