Targeting inflammation using genetic reprogramming in mRNA display — ASN Events
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  3. Targeting inflammation using genetic reprogramming in mRNA display

Targeting inflammation using genetic reprogramming in mRNA display (#392)

Belinda Zhang 1 2 , Jason Johansen-Leete 1 2 , Richard J Payne 1 2
  1. School of Chemistry, The University of Sydney, NSW
  2. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, NSW

Inflammation is a vital process to eliminate pathogens and kickstart injury repair, however dysregulation of this response can lead to chronic inflammation and disease.1 Recruitment of immune cells to sites of inflammation is orchestrated by a network of chemoattractant proteins known as chemokines and their cell-surface receptors.2, 3 Given their critical role in driving inflammation, inhibition of chemokine-receptor interactions presents an emerging approach for the treatment of inflammatory disease. This strategy has natural precedence – chemokine-binding proteins (CKBPs) are employed in the chemical arsenal of both viruses and parasitic organisms to allow for the evasion of immune detection.4-6 Many of these pathogenic organisms use tyrosine sulfation as a post-translational modification (PTM) to improve the binding affinity of such CKBPs to their chemokine targets, by mimicking the native tyrosine sulfation of chemokine receptors.7 Recent advances in peptide display technologies have led to the development of a RaPID mRNA display platform with genetic reprogramming to discover potent cyclic peptide ligands through iterative rounds of screening against an immobilised protein target.8 Here, we have sought to mimic the binding interactions of native chemokine receptors by incorporating sulfated tyrosine into a RaPID selection against native CCL25.

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  2. Hughes, C. E.; Nibbs, R. J. B. A guide to chemokines and their receptors. FEBS J. 2018, 285 (16), 2944-2971. DOI: 10.1111/febs.14466.
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  7. Franck, C.; Foster, S. R.; Johansen-Leete, J.; Chowdhury, S.; Cielesh, M.; Bhusal, R. P.; Mackay, J. P.; Larance, M.; Stone, M. J.; Payne, R. J. Semisynthesis of an evasin from tick saliva reveals a critical role of tyrosine sulfation for chemokine binding and inhibition. Proc. Natl. Acad. Sci. U. S. A. 2020, 117 (23), 12657-12664. DOI: 10.1073/pnas.2000605117.
  8. Johansen-Leete, J.; Passioura, T.; Foster, S. R.; Bhusal, R. P.; Ford, D. J.; Liu, M.; Jongkees, S. A. K.; Suga, H.; Stone, M. J.; Payne, R. J. Discovery of Potent Cyclic Sulfopeptide Chemokine Inhibitors via Reprogrammed Genetic Code mRNA Display. J. Am. Chem. Soc. 2020, 142 (20), 9141-9146. DOI: 10.1021/jacs.0c03152.
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