Discovery and pharmacophoric characterization of chemokine network inhibitors using phage-display, saturation mutagenesis and computational modelling.
Nat Commun
; 14(1): 5763, 2023 09 16.
Article
em En
| MEDLINE
| ID: mdl-37717048
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Bacteriófagos
/
Quimiocinas
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article