Discovery and pharmacophoric characterization of chemokine network inhibitors using phage-display, saturation mutagenesis and computational modelling

Serena Vales, Jhanna Kryukova, Soumyanetra Chandra, Gintare Smagurauskaite, Megan Payne, Charlie J. Clark, Katrin Hafner, Philomena Mburu, Stepan Denisov, Graham Davies, Carlos Outeiral, Charlotte M. Deane, Garrett M. Morris and Shoumo Bhattacharya ()
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Serena Vales: University of Oxford
Jhanna Kryukova: University of Oxford
Soumyanetra Chandra: University of Oxford
Gintare Smagurauskaite: University of Oxford
Megan Payne: University of Oxford
Charlie J. Clark: University of Oxford
Katrin Hafner: University of Oxford
Philomena Mburu: University of Oxford
Stepan Denisov: University of Oxford
Graham Davies: University of Oxford
Carlos Outeiral: University of Oxford
Charlotte M. Deane: University of Oxford
Garrett M. Morris: University of Oxford
Shoumo Bhattacharya: University of Oxford

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract CC and CXC-chemokines are the primary drivers of chemotaxis in inflammation, but chemokine network redundancy thwarts pharmacological intervention. Tick evasins promiscuously bind CC and CXC-chemokines, overcoming redundancy. Here we show that short peptides that promiscuously bind both chemokine classes can be identified from evasins by phage-display screening performed with multiple chemokines in parallel. We identify two conserved motifs within these peptides and show using saturation-mutagenesis phage-display and chemotaxis studies of an exemplar peptide that an anionic patch in the first motif and hydrophobic, aromatic and cysteine residues in the second are functionally necessary. AlphaFold2-Multimer modelling suggests that the peptide occludes distinct receptor-binding regions in CC and in CXC-chemokines, with the first and second motifs contributing ionic and hydrophobic interactions respectively. Our results indicate that peptides with broad-spectrum anti-chemokine activity and therapeutic potential may be identified from evasins, and the pharmacophore characterised by phage display, saturation mutagenesis and computational modelling.

Date: 2023
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DOI: 10.1038/s41467-023-41488-z

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