Macrocyclic peptide probes for immunomodulatory protein CD59: potent modulators of bacterial toxin activity and antibody-dependent cytotoxicity
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2025-07-01
Date Acceptance
2025-04-23
Citation
Angewandte Chemie, 2025, 137 (27)
ISSN
0044-8249
Publisher
Wiley
Journal / Book Title
Angewandte Chemie
Volume
137
Issue
27
Copyright Statement
© 2025 The Author(s). Angewandte Chemie published by Wiley-VCH GmbH This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Publication Status
Published
Article Number
e202422673
Date Publish Online
2025-04-24