Oxetane grafts site-selectively installed on native disulfides enhance protein stability and activity in vivo
Angewandte Chemie - International Edition
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Martínez-Sáez, N., Sun, S., Oldrini, D., Sormanni, P., Boutureira, O., Carboni, F., Compañón, I., et al. (2017). Oxetane grafts site-selectively installed on native disulfides enhance protein stability and activity in vivo. Angewandte Chemie - International Edition, 56 (47), 14963-14967. https://doi.org/10.1002/anie.201708847
Here we show that a four-membered oxygen ring – oxetane – can be readily grafted into native peptides and proteins through site-selective bis-alkylation of cysteine residues present as disulfides under mild and biocompatible conditions. The selective installation of the oxetane graft enhances stability and activity, as demonstrated for a range of biologically relevant cyclic peptides, including somatostatin, proteins and antibodies, such as a Fab arm of the antibody Herceptin® and a designed antibody DesAb-A against the human Amyloid- peptide. Markedly, oxetane grafting of the genetically detoxified diphtheria toxin CRM197 improves significantly the immunogenicity of this protein in mice, which illustrates the general utility of this strategy to modulate the stability and biological activity of therapeutic proteins containing disulfides in their structures.
antibodies, disulfides, immunogenic proteins, oxetanes, stapling
We thank FCT Portugal, the EU (Marie Curie IEF to O.B.; Marie Sklodowska-Curie ITN GlycoVax to G.J.L.B. and R.A.), Cambridge Trust and China Scholarship Council (PhD studentship to S.S.), MINECO (CTQ2015-67727-R and Salvador de Madariaga mobility grant to F.Corzana) and the EPSRC for funding.
Royal Society (uf110046)
European Commission Horizon 2020 (H2020) ERC (676832)
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External DOI: https://doi.org/10.1002/anie.201708847
This record's URL: https://www.repository.cam.ac.uk/handle/1810/273533
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
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