Stoichiometric and irreversible cysteine-selective protein modification using carbonylacrylic reagents

Barbara Bernardim, Pedro M.S.D. Cal, Maria J. Matos, Bruno L. Oliveira, Nuria Martínez-Sáez, Inês S. Albuquerque, Elizabeth Perkins, Francisco Corzana, Antonio C.B. Burtoloso, Gonzalo Jiménez-Osés and Gonçalo J. L. Bernardes ()
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Barbara Bernardim: University of Cambridge
Pedro M.S.D. Cal: University of Cambridge
Maria J. Matos: University of Cambridge
Bruno L. Oliveira: University of Cambridge
Nuria Martínez-Sáez: University of Cambridge
Inês S. Albuquerque: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa
Elizabeth Perkins: Albumedix Ltd, Castle Court
Francisco Corzana: University of Cambridge
Antonio C.B. Burtoloso: Instituto de Química de São Carlos, Universidade de São Paulo
Gonzalo Jiménez-Osés: Universidad de La Rioja, Centro de Investigacioón en Síntesis Química
Gonçalo J. L. Bernardes: University of Cambridge

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: Abstract Maleimides remain the reagents of choice for the preparation of therapeutic and imaging protein conjugates despite the known instability of the resulting products that undergo thiol-exchange reactions in vivo. Here we present the rational design of carbonylacrylic reagents for chemoselective cysteine bioconjugation. These reagents undergo rapid thiol Michael-addition under biocompatible conditions in stoichiometric amounts. When using carbonylacrylic reagents equipped with PEG or fluorophore moieties, this method enables access to protein and antibody conjugates precisely modified at pre-determined sites. Importantly, the conjugates formed are resistant to degradation in plasma and are biologically functional, as demonstrated by the selective imaging and detection of apoptotic and HER2+ cells, respectively. The straightforward preparation, stoichiometric use and exquisite cysteine selectivity of the carbonylacrylic reagents combined with the stability of the products and the availability of biologically relevant cysteine-tagged proteins make this method suitable for the routine preparation of chemically defined conjugates for in vivo applications.

Date: 2016
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DOI: 10.1038/ncomms13128

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