Macrocyclic Peptide Probes for Immunomodulatory Protein CD59: Potent Modulators of Bacterial Toxin Activity and Antibody‐Dependent Cytotoxicity

TL;DR

Researchers developed new macrocyclic peptides that strongly bind to CD59, a protein involved in immune regulation and disease, offering potential for treating related conditions.

Contribution

The study introduces macrocyclic peptides as a novel strategy to target CD59 with low nanomolar affinity and functional activity.

Findings

Macrocyclic peptide CP-06 binds CD59 through an intermolecular beta-sheet, mimicking natural interactions.

Dimeric and lipidated versions of CP-06 effectively inhibit CD59 activity in cellular contexts.

These peptides modulate both complement-mediated cell killing and bacterial toxin activity.

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.

This study presents novel macrocyclic peptides with low nanomolar affinity for CD59, an immunomodulatory cell surface receptor associated with human disease. Crystallographic and structure‐activity relationship (SAR) studies reveal peptide CP‐06 mimics the binding of biologically relevant CD59 interaction partners. Dimeric and lipidated CP‐06 analogues control both complement‐mediated killing of human cells and lytic activity of bacterial virulence factors via CD59 inhibition.

Figures