Lay summary
Site-specific protein modification is fundamental to many areas of biology. The modification of protein drugs by attachment of sugars or PEG chains, is crucial to their effectiveness and potency. Despite the efforts of the ongoing research, the synthesis of uniformly modified proteins remains one of the greatest challenges in organic chemistry.

Based on very recent progress in the field, we propose an approach towards copper-free click chemistry on proteins, by co-expression of pyrrolysine derivatives bearing a Norbornene moeity, to later react them under mild conditions on the protein surface.

Existing methods on unnatural amino acid insertion into proteins can be applied in the preparation of novel proteins, allowing the incorporation of functional unnatural amino acids within a highly complex chemical environment. A controllable and reliable copper-free click reaction on proteins will provide not only more stable and potent proteins in vivo, but also, this strategy will be of high importance in biomedical research.