Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 142, Issue 11, Pages 4965-4969Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.9b12280
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- Japan Society for the Promotion of Science [18H02080]
- Japan Science and Technology Agency (JST) PRESTO [JPMJPR14K3]
- JST CREST [JPMJCR12L2]
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Because gamma-amino acids generally undergo rapid self-cyclization upon esterification on the carboxyl group, for example, gamma-aminoacyl-tRNA, there are no reports of the ribosomal elongation of gamma-amino acids to the best of our knowledge. To avoid such self-cyclization, we utilized cyclic gamma-amino acids and demonstrated their elongation into a peptide chain. Although the incorporation of the cyclic gamma-amino acids is intrinsically slow, we here show that the combination of elongation factor P and engineered tRNAs improves cyclic gamma-amino acid incorporation efficiency. Via this method, thioether-macrocyclic peptides containing not only cyclic gamma-amino acids but also D-alpha-, N-methyl-alpha-, and cyclic beta-amino acids were expressed under the reprogrammed genetic code. Ribosomally synthesized macrocyclic peptide libraries containing cyclic gamma-amino acids should be applicable to in vitro screening methodologies such as mRNA display for discovering novel peptide drugs.
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