Oxetane grafts site-selectively installed on native disulfides enhance protein stability and activity in vivo
Authors
Martínez-Sáez, N
Oldrini, D
Boutureira, O
Carboni, F
Compañón, I
Corzana, F
Adamo, R
Publication Date
2017-11-20Journal Title
Angewandte Chemie - International Edition
ISSN
1433-7851
Publisher
Wiley
Volume
56
Issue
47
Pages
14963-14967
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
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
Abstract
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.
Keywords
antibodies, disulfides, immunogenic proteins, oxetanes, stapling
Sponsorship
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.
Funder references
EPSRC (EP/M003647/1)
Royal Society (uf110046)
European Commission Horizon 2020 (H2020) ERC (676832)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1002/anie.201708847
This record's URL: https://www.repository.cam.ac.uk/handle/1810/273533
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