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Oxetane Grafts Installed Site‐Selectively on Native Disulfides to Enhance Protein Stability and Activity In Vivo
Author(s) -
MartínezSáez Nuria,
Sun Shuang,
Oldrini Davide,
Sormanni Pietro,
Boutureira Omar,
Carboni Filippo,
Compañón Ismael,
Deery Michael J.,
Vendruscolo Michele,
Corzana Francisco,
Adamo Roberto,
Bernardes Gonçalo J. L.
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201708847
Subject(s) - oxetane , chemistry , immunogenicity , peptide , in vivo , cysteine , in vitro , diphtheria toxin , biochemistry , peptidomimetic , cyclic peptide , antibody , combinatorial chemistry , toxin , enzyme , biology , organic chemistry , microbiology and biotechnology , immunology
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‐Aβ against the human Amyloid‐β peptide. Oxetane grafting of the genetically detoxified diphtheria toxin CRM 197 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.