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Oxetane grafts site-selectively installed on native disulfides enhance protein stability and activity in vivo

Martínez-Sáez, N and Sun, S and Oldrini, D and Sormanni, P and Boutureira, O and Carboni, F and Compañón, I and Deery, MJ and Vendruscolo, M and Corzana, F and Adamo, R and Lopes Bernardes, GJ (2017) Oxetane grafts site-selectively installed on native disulfides enhance protein stability and activity in vivo. Angewandte Chemie - International Edition, 56. pp. 14963-14967.

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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.

Item Type: Article
Uncontrolled Keywords: antibodies disulfides immunogenic proteins oxetanes stapling
Subjects: UNSPECIFIED
Divisions: UNSPECIFIED
Depositing User: Cron Job
Date Deposited: 25 Jun 2019 02:49
Last Modified: 10 Apr 2021 22:36
DOI: 10.1002/anie.201708847