There are many good reasons to functionalize proteins, for example, modifying their physicochemical properties or synthesizing the latest antibody–drug conjugate. Proteins are highly reactive and unfortunately do not come pre-installed with protecting groups. This means that if you want to control which amino acid residue you modify, you are limited either by the protein's cysteine count (this amino acid contains a reactive thiol group) or to using challenging molecular biology techniques, enzymes, or arsenic chemistry.
Bradley Pentelute and colleagues, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA, have discovered, through screening peptide libraries, a tetrapeptide sequence (FCPF, nicknamed the "π-clamp") that reacts by aromatic nucleophilic substitution with perfluoroaryl groups. This reaction does not normally occur in water, and is orthogonal with other protein-labeling chemistry.
The team reacted proteins genetically encoded with this sequence with a range of chemical entities including a fluorophore and a peptide sequence. They showed that proteins fitted with the π-clamp, even enzymes that function through a reactive cysteine residue, could be labeled in a site-selective manner. Furthermore, the researchers reacted the monoclonal antibody trastuzumab with the synthetic antineoplastic agent monomethyl auristatin F and used the resulting antibody–drug conjugate to selectively kill breast cancer cells.
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