Oxetane Grafts Installed Site-Selectively on Native Disulfides to Enhance Protein Stability and Activity In Vivo

  1. Martínez-Sáez, N. 1
  2. Sun, S. 1
  3. Oldrini, D. 3
  4. Sormanni, P. 1
  5. Boutureira, O. 1
  6. Carboni, F. 3
  7. Compañón, I. 2
  8. Deery, M.J. 1
  9. Vendruscolo, M. 1
  10. Corzana, F. 2
  11. Adamo, R. 3
  12. Bernardes, G.J.L. 14
  1. 1 University of Cambridge
    info

    University of Cambridge

    Cambridge, Reino Unido

    ROR https://ror.org/013meh722

  2. 2 Universidad de La Rioja
    info

    Universidad de La Rioja

    Logroño, España

    ROR https://ror.org/0553yr311

  3. 3 GSK Vaccines, Via Fiorentina 1, Siena, Italy
  4. 4 Universidade de Lisboa
    info

    Universidade de Lisboa

    Lisboa, Portugal

    ROR https://ror.org/01c27hj86

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Revista:
Angewandte Chemie International

ISSN: 1433-7851

Any de publicació: 2017

Volum: 56

Número: 47

Pàgines: 14963-14967

Tipus: Article

DOI: 10.1002/ANIE.201708847 SCOPUS: 2-s2.0-85031759077 WoS: WOS:000415211500029 GOOGLE SCHOLAR

Altres publicacions en: Angewandte Chemie International

Objectius de Desenvolupament Sostenible

Resum

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 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. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.