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Citation

BibTex format

@article{Tate:2025:10.1002/ange.202422673,
author = {Tate, EW and Bickel, JK and Ahmed, AIS and Pidd, AB and Morgan, RM and McAllister, TE and Horrell, SM and Couves, EC and Nagaraj, H and Bartlett, EJ and El, Omari K and Kawamura, A and Bubeck, D},
doi = {10.1002/ange.202422673},
journal = {Angewandte Chemie},
title = {Macrocyclic peptide probes for immunomodulatory protein CD59: potent modulators of bacterial toxin activity and antibody-dependent cytotoxicity},
url = {http://dx.doi.org/10.1002/ange.202422673},
year = {2025}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Tate,EW
AU  - Bickel,JK
AU  - Ahmed,AIS
AU  - Pidd,AB
AU  - Morgan,RM
AU  - McAllister,TE
AU  - Horrell,SM
AU  - Couves,EC
AU  - Nagaraj,H
AU  - Bartlett,EJ
AU  - El,Omari K
AU  - Kawamura,A
AU  - Bubeck,D
DO  - 10.1002/ange.202422673
PY  - 2025///
SN  - 0044-8249
TI  - Macrocyclic peptide probes for immunomodulatory protein CD59: potent modulators of bacterial toxin activity and antibody-dependent cytotoxicity
T2  - Angewandte Chemie
UR  - http://dx.doi.org/10.1002/ange.202422673
UR  - https://doi.org/10.1002/ange.202422673
ER  -
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Contact

Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ

e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821