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Ribosomal Incorporation of Consecutive β-Amino Acids

Katoh, Takayuki, Suga, Hiroaki
Journal of the American Chemical Society 2018 v.140 no.38 pp. 12159-12167
Escherichia coli, amino acids, binding capacity, drugs, models, nanomaterials, peptides
Due to their unique characteristics, which are not shared by canonical α-peptides, peptides that contain stretches of consecutive β-amino acids are attractive scaffolds for novel peptide drugs and nanomaterials. Although ribosomal incorporation of single or nonconsecutive β-amino acids into peptides has previously been reported, the incorporation of consecutive β-amino acids has not yet been accomplished. This is primarily due to their incompatibility with the ribosomal translation system. Here, we took advantage of engineered β-aminoacyl-tRNAs bearing optimized T-stem and D-arm motifs for enhancing binding affinity to EF-Tu and EF-P, respectively. Combined with a reconstituted E. coli translation system and optimized translation factor concentrations, up to seven consecutive β-amino acids could be incorporated into a model peptide. Furthermore, the synthesis of macrocyclic β-peptides closed by a thioether bond between two d-α-amino acids is also demonstrated. This represents the first example of the ribosomal synthesis of peptides containing stretches of consecutive β-amino acids.