Because γ-amino acids generally undergo rapid self-cyclization upon esterification on the carboxyl group, for example, γ-aminoacyl-tRNA, there are no reports of the ribosomal elongation of γ-amino acids. To avoid such self-cyclization, researchers in the Suga lab utilized cyclic γ-amino acids and demonstrate their elongation into a peptide chain.

Although the incorporation of the cyclic γ-amino acids is intrinsically slow, they have shown that the combination of elongation factor P and engineered tRNAs improves cyclic γ-amino acid incorporation efficiency. Via this method, thioether-macrocyclic peptides containing not only cyclic γ-amino acids but also d-α-, N-methyl-α-, and cyclic β-amino acids were expressed under the reprogrammed genetic code.

Ribosomally synthesized macrocyclic peptide libraries containing cyclic γ-amino acids should be applicable to in vitro screening methodologies such as mRNA display for discovering novel peptide drugs.

Title:
Ribosomal Elongation of Cyclic γ‑Amino Acids using a Reprogrammed Genetic Code
Authors:
Takayuki Katoh and Hiroaki Suga
Citation:
J. Am. Chem. Soc. 2020, 142, 4965−4969
URL:
https://pubs.acs.org/doi/10.1021/jacs.9b12280