Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms13128
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Funding
- FAPESP [2012/22274-2, BEPE 2015/07509-1, 2013/25504-1]
- Xunta de Galicia
- FCT Portugal [SFRH/BPD/103172/2014, SFRH/BD/111556/2015]
- EU (Marie-Sklodowska Curie ITN Protein Conjugates)
- EPSRC, MECD ('Salvador Madariaga' mobility grant) [PRX15/00638]
- MINECO [CTQ2015-70524-R, RYC-2013-14706]
- European Research Council
- EPSRC [EP/M003647/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/M003647/1] Funding Source: researchfish
- Fundação para a Ciência e a Tecnologia [SFRH/BD/111556/2015] Funding Source: FCT
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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.
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