Site-selective installation of an electrophilic handle on proteins for bioconjugation

Bioorganic & Medicinal Chemistry
Bernadette LeeGonçalo J L Bernardes

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.

Citations

May 7, 2019·Chemical Science·Enrique Gil de MontesGonçalo J L Bernardes
Jan 26, 2020·Angewandte Chemie·Enrique Gil de MontesGonçalo J L Bernardes
Jun 17, 2020·Organic & Biomolecular Chemistry·Neelesh C ReddyVishal Rai
Jun 29, 2021·Chemical Communications : Chem Comm·Mohan KumarVishal Rai
Jul 16, 2021·Bioconjugate Chemistry·Zbigniew ZawadaGonçalo J L Bernardes
Apr 28, 2020·Journal of the American Chemical Society·Alice L BaumannChristian P R Hackenberger
May 28, 2020·Journal of the American Chemical Society·Bruno L OliveiraGonçalo J L Bernardes

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