Site-Selective Modification of Proteins with Oxetanes

  1. Boutureira, O. 13
  2. Martínez-Sáez, N. 3
  3. Brindle, K.M. 35
  4. Neves, A.A. 5
  5. Corzana, F. 23
  6. Bernardes, G.J.L. 34
  1. 1 Universitat Rovira i Virgili
    info

    Universitat Rovira i Virgili

    Tarragona, España

    ROR https://ror.org/00g5sqv46

  2. 2 Universidad de La Rioja
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    Universidad de La Rioja

    Logroño, España

    ROR https://ror.org/0553yr311

  3. 3 University of Cambridge
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    University of Cambridge

    Cambridge, Reino Unido

    ROR https://ror.org/013meh722

  4. 4 Universidade de Lisboa
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    Universidade de Lisboa

    Lisboa, Portugal

    ROR https://ror.org/01c27hj86

  5. 5 Cancer Research UK Cambridge Institute
    info

    Cancer Research UK Cambridge Institute

    Cambridge, Reino Unido

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Revista:
Chemistry - A European Journal

ISSN: 0947-6539

Año de publicación: 2017

Volumen: 23

Número: 27

Páginas: 6483-6489

Tipo: Artículo

DOI: 10.1002/CHEM.201700745 SCOPUS: 2-s2.0-85016804652 WoS: WOS:000401160100002 GOOGLE SCHOLAR

Otras publicaciones en: Chemistry - A European Journal

Resumen

Oxetanes are four-membered ring oxygen heterocycles that are advantageously used in medicinal chemistry as modulators of physicochemical properties of small molecules. Herein, we present a simple method for the incorporation of oxetanes into proteins through chemoselective alkylation of cysteine. We demonstrate a broad substrate scope by reacting proteins used as apoptotic markers and in drug formulation, and a therapeutic antibody with a series of 3-oxetane bromides, enabling the identification of novel handles (S-to-S/N rigid, non-aromatic, and soluble linker) and reactivity modes (temporary cysteine protecting group), while maintaining their intrinsic activity. The possibility to conjugate oxetane motifs into full-length proteins has potential to identify novel drug candidates as the next-generation of peptide/protein therapeutics with improved physicochemical and biological properties. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.