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bioRxiv · 10.64898/2026.08.12.744392

Phage Display-Derived Cyclic Peptides as Ligand-Specific Modulators for β2-Integrin Receptors

Sommer-Plüss, C. J.·Vogt, S. A.·Ciullo, L.·Mancuso, R.·Götze-Ebert, T.·Kehr, L.·Ricklin, D.·Lamers, C.
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Abstract

The leukocyte-specific {beta}2-integrin receptor family exerts a wide range of functions: {beta}2-integrins are involved in leukocyte trafficking, where they mediate cell adhesion during inflammatory responses via binding to ICAM-1, ICAM-2, or JAM-C. Furthermore, they are essential for the recognition and phagocytosis of pathogens opsonized by complement. Accordingly, the {beta}2-integrin family is known to be involved in autoimmune and inflammatory diseases, such as systemic lupus erythematosus. Owing to their complex biology, involving multiple conformational transitions, different signaling pathways, and a broad spectrum of ligands, the development of {beta}2-integrin-targeted probes and therapeutics has remained challenging. We aimed to develop macrocyclic peptides, derived from phage display screening, which can be used to unravel ligand binding profiles of {beta}2-integrins with an emphasis on the I domain. The selection of suitable lead peptides, and the characterization of their interaction profiles with different I domains, was enabled by an established in-vitro assay platform. Various peptide sequences were enriched during several rounds of phage display against the I-domain of CR3, of which two peptides with particularly low micromolar binding affinity were further characterized. Both peptides showed direct binding to {beta}2-integrin I-domains and, in a competitive assay, dose-dependent inhibition of the I-domains interactions with their main ligands iC3b and ICAM-1, respectively. These ligand-interfering properties were confirmed in bead- and cell-based adhesion assays. The modulators developed here are expected to provide valuable insight into the (patho-)physiology of CR3 and the other members of the {beta}2-integrin family, as the two peptides were able to compete with different ligands. In the future, this may help to identify potential therapeutic approaches for autoimmune, inflammatory, and age-related diseases.

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Sommer-Plüss, C. J., Vogt, S. A., Ciullo, L., Mancuso, R., Götze-Ebert, T., Kehr, L., Ricklin, D., Lamers, C.. 2026-08-17. Phage Display-Derived Cyclic Peptides as Ligand-Specific Modulators for β2-Integrin Receptors. https://doi.org/10.64898/2026.08.12.744392

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