Discovery of Potent Cyclic Sulfopeptide Chemokine Inhibitors via Reprogrammed Genetic Code mRNA Display

Targeting chemokine signaling is an attractive avenue for the treatment of inflammatory disorders. Tyrosine sulfation is an important post-translational modification (PTM) that enhances chemokine–receptor binding and is also utilized by a number of pathogenic organisms to improve the binding affinit...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2020-05, Vol.142 (20), p.9141-9146
Main Authors: Johansen-Leete, Jason, Passioura, Toby, Foster, Simon R, Bhusal, Ram Prasad, Ford, Daniel J, Liu, Minglong, Jongkees, Seino A. K, Suga, Hiroaki, Stone, Martin J, Payne, Richard J
Format: Article
Language:English
Subjects:
Chemokine CCL11 - antagonists & inhibitors
Chemokine CCL11 - genetics
Chemokine CCL11 - metabolism
Drug Discovery
Humans
Molecular Structure
Peptides - chemistry
Peptides - pharmacology
RNA, Messenger - drug effects
RNA, Messenger - genetics
RNA, Messenger - metabolism
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Summary:Targeting chemokine signaling is an attractive avenue for the treatment of inflammatory disorders. Tyrosine sulfation is an important post-translational modification (PTM) that enhances chemokine–receptor binding and is also utilized by a number of pathogenic organisms to improve the binding affinity of immune-suppressive chemokine binding proteins (CKBPs). Here we report the display selection of tyrosine-sulfated cyclic peptides using a reprogrammed genetic code to discover high-affinity ligands for the chemokine CCL11 (eotaxin-1). The selected cyclic sulfopeptides possess high affinity for the target chemokine (as well as one or more of the related family members CCL2, CCL7 and CCL24) and inhibit CCL11 activation of CC chemokine receptor 3 (CCR3). This work demonstrates the utility of exploiting native PTMs as binding motifs for the generation of new leads for medicinal chemistry.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.0c03152