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

Jason Johansen-Leete; Toby Passioura; Simon R Foster; Ram Prasad Bhusal; Daniel J Ford; Minglong Liu; Seino A K Jongkees; Hiroaki Suga; Martin J Stone; Richard J Payne

doi:10.1021/jacs.0c03152

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

J Am Chem Soc. 2020 May 20;142(20):9141-9146. doi: 10.1021/jacs.0c03152. Epub 2020 May 7.

Authors

Jason Johansen-Leete¹, Toby Passioura^{1

2

3

4}, Simon R Foster⁵, Ram Prasad Bhusal⁵, Daniel J Ford¹, Minglong Liu⁶, Seino A K Jongkees⁶, Hiroaki Suga⁴, Martin J Stone⁵, Richard J Payne^{1

7}

Affiliations

¹ School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
² School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia.
³ Sydney Analytical, The University of Sydney, Sydney, NSW 2006, Australia.
⁴ Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
⁵ Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
⁶ Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands.
⁷ Australian Research Council Centre of Excellence for Innovations in Peptide and Protein ScienceThe University of Sydney, Sydney, NSW 2006, Australia.

PMID: 32330017
DOI: 10.1021/jacs.0c03152

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

CCL11 protein, human
Chemokine CCL11
Peptides
RNA, Messenger