Protein conjugation with genetically encoded unnatural amino acids

Abstract

The site-specific incorporation of unnatural amino acids with orthogonal chemical reactivity into proteins enables the synthesis of structurally defined protein conjugates. Amino acids containing ketone, azide, alkyne, alkene, and tetrazine side chains can be genetically encoded in response to nonsense and frameshift codons. These bio-orthogonal chemical handles allow precise control over the site and stoichiometry of conjugation, and have enabled medicinal chemistry-like optimization of the physical and biological properties of protein conjugates, especially the next-generation protein therapeutics.

Figure 1

Scheme for the genetic incorporation of unnatural amino acids.

Figure 2

UAAs used for site-specific protein conjugation.

Figure 3

Protein conjugates synthesized with unnatural amino acids and examples of their applications.