Therapeutic Applications of an Expanded Genetic Code

To date, over 100 noncanonical amino acids (ncAAs) have been genetically encoded in living cells in order to expand the functional repertoire of the canonical 20 amino acids. More recently, this technology has been expanded to the field of protein therapeutics, where traditional chemical methods typically result in heterogeneous mixtures of proteins. The site‐specific incorporation of ncAAs with orthogonal chemical groups allows unprecedented control over the site of conjugation and the stoichiometry, thus facilitating the rational optimization of the biological functions and/or pharmacokinetics of biologics. Herein, we discuss the recent contribution of ncAA technology in enhancing the pharmacological properties of current protein therapeutics as well as developing novel therapeutic modalities. Expanding the code: The genetic encoding of noncanonical amino acids allows for the site‐specific introduction of reactive moieties that are typically unavailable to native proteins. In this review, we discuss how this technology has been adopted to overcome existing challenges in current protein therapeutics and to develop novel therapeutic modalities.