Site-selective installation of an electrophilic handle on proteins for bioconjugation |
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Authors: | Bernadette Lee Shuang Sun Ester Jiménez-Moreno André A. Neves Gonçalo J.L. Bernardes |
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Affiliation: | 1. Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK;2. Li Ka Shing Centre, Cancer Research UK Cambridge Institute, Robinson Way, CB2 0RE Cambridge, UK;3. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal |
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Abstract: | Site-selective protein modification strategies can be used to insert non-natural functional groups into protein structures. Herein, we report on the use of the bis-electrophile 3-bromo-2-bromomethyl-1-propene as a reagent to introduce an electrophilic handle at cysteine residues under mild conditions. This method is demonstrated on a variety of proteins containing a solvent-exposed cysteine residue, including an anti-HER2 nanobody. Chemically distinct protein conjugates are then efficiently formed through further reaction of the electrophilic site with various nucleophiles, including thiols and amines. The resulting chemically-defined conjugates are highly stable in the presence of glutathione or human plasma and retain both the structure and function of the native protein. |
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Keywords: | Bioconjugation Cysteine alkylation Electrophilic handle Protein engineering Selective labelling |
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