Expansion of the Genetic Code: Unnatural Amino Acids and their Applications

The genetic codes of every known organism involve the same 20 amino acid building blocks, with a limited number of functional groups, using triplet codons generated from A, G, C, and T. Clearly, there is a need for additional functional groups in proteins, as evidenced by a large number of post-translational modifications, and cofactors, as well as the rare occurrence of the unnatural amino acids seleno cysteine and pyrrolo lysine.  The historical development of synthetic or semi-synthetic methods for the introduction of unnatural amino acids into peptide and proteins by Offord and Kaiser, paved the way for the development of new methods for site-specific incorporation of more unnatural amino acids into proteins by Schultz et al., towards expanding the genetic code. An increasing level of interest from various research groups has accelerated progress in designing unnatural amino acids. However, many reported unnatural amino acids were found to be unsuitable for introducing novel biological properties to proteins, or did not contain functionality suitable for labelling proteins. These unnatural amino acids were mainly applied in bioanalytical applications. However, little attention has been paid to develop fluorescent unnatural amino acids (FUAA) or fluorescently-labelled UAA for genetic encoding or generating labelled proteins/peptide to study conformational or diverse functional realms.

Given the recent growth in research aimed at expanding the genetic code, we devote this Research Topic in Frontiers in Chemistry to showcasing these advances and the new technologies they have enabled. Currently, over 150 non-canonical amino acids (ncAAs) have been site-specifically introduced into proteins with high efficiency using an orthogonal tRNA synthetase pair in various organisms. These efforts have enabled the generation of proteins with new building blocks beyond those specified by the genetic code, and could provide powerful tools to generate proteins or even entire organisms with novel functions. 

This Research Topic will focus on the synthesis and application of unnatural amino acids with novel properties. We welcome authors to submit their Original Research works and Review articles on recent topics related to expanding the genetic code, including new design concepts, syntheses, and applications. Potential themes include, but are not limited to:

 • Design and synthesis of unnatural amino acids/fluorescent amino acids
 • Design and synthesis of small side-chain modified unnatural amino acids
 • IR-responsive unnatural amino acids in peptides/proteins
 • Site-specific incorporation of UAA into proteins
 • In-vitro genetic code expansion
 • Engineering tRNA and tRNA-synthetase for site-specific introduction
 • Probing protein structure/function, and the role of post-translational modifications with UAA
 • Identifying and regulating protein activity with UAAs
 • Improving proteins’ immunogenicity and overcoming self-tolerance with UAA
 • Application of unnatural amino acids/peptides/proteins in diagnostics, sensors, and nanotechnology