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Updated: Jun 8, 2026

Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors
Published on: September 13, 2013
Discovery of Selective Cyclic d-Sulfopeptide Ligands of the Chemokine CCL22 via Mirror-Image mRNA Display with
Belinda B Zhang1,2, Katriona Harrison1,2, Yichen Zhong1,2
1School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
Abstract:
Chemokines are small proteins involved in recruiting leukocytes to sites of inflammation via interactions with specific cell surface receptors. CCL22 is a chemokine known to play a critical role in inflammatory diseases such as atopic dermatitis and asthma; inhibition of this chemokine therefore represents an attractive therapeutic strategy. Herein, we describe the discovery of cyclic d-sulfopeptide inhibitors of CCL22 identified through mirror-image mRNA display with genetic reprogramming. Chemical synthesis of mirror-image d-CCL22 enabled screening of a cyclic peptide library comprised of all l-amino acids, with reprogramming of l-sulfotyrosine to mimic the presence of this post-translational modification on native chemokine receptors. Enriched macrocyclic peptides were prepared in their mirror-image d-form and assessed for binding against native l-CCL22. The most potent ligand, a plasma-stable d-cyclic peptide bearing four d-sulfotyrosine residues, exhibited nanomolar affinity for CCL22, high selectivity over other chemokines, and nanomolar inhibition of CCL22 signaling through CCR4. This work highlights the vast potential of mirror-image mRNA display technology for discovering proteolytically stable d-peptide inhibitors of protein-protein interactions relevant across a range of therapeutic indications.
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