Proximity-driven site-specific cyclization of phage-displayed peptides

Libby Brown, Aldrin V. Vidal, Ana Laura Dias, Tiago Rodrigues, Anna Sigurdardottir, Toby Journeaux, Siobhan O’Brien, Thomas V. Murray, Peter Ravn, Monika Papworth and Gonçalo J. L. Bernardes ()
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Libby Brown: University of Cambridge
Aldrin V. Vidal: University of Cambridge
Ana Laura Dias: Universidade de Lisboa
Tiago Rodrigues: Universidade de Lisboa
Anna Sigurdardottir: The Discovery Centre; Cambridge Biomedical Campus
Toby Journeaux: University of Cambridge
Siobhan O’Brien: The Discovery Centre; Cambridge Biomedical Campus
Thomas V. Murray: The Discovery Centre; Cambridge Biomedical Campus
Peter Ravn: The Discovery Centre; Cambridge Biomedical Campus
Monika Papworth: The Discovery Centre; Cambridge Biomedical Campus
Gonçalo J. L. Bernardes: University of Cambridge

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Cyclization provides a general strategy for improving the proteolytic stability, cell membrane permeability and target binding affinity of peptides. Insertion of a stable, non-reducible linker into a disulphide bond is a commonly used approach for cyclizing phage-displayed peptides. However, among the vast collection of cysteine reactive linkers available, few provide the selectivity required to target specific cysteine residues within the peptide in the phage display system, whilst sparing those on the phage capsid. Here, we report the development of a cyclopropenone-based proximity-driven chemical linker that can efficiently cyclize synthetic peptides and peptides fused to a phage-coat protein, and cyclize phage-displayed peptides in a site-specific manner, with no disruption to phage infectivity. Our cyclization strategy enables the construction of stable, highly diverse phage display libraries. These libraries can be used for the selection of high-affinity cyclic peptide binders, as exemplified through model selections on streptavidin and the therapeutic target αvβ3.

Date: 2024
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DOI: 10.1038/s41467-024-51610-4

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