チアゾール含有環状ペプチドの翻訳合成法

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The synthesis of proposed unnatural amino acid derivatives were attempted but failed. Therefore, focus was diverted towards the synthesis of peptides containing a backbone thioamide moiety.Ribosome-mediated thioamide bond catalysis was demonstrated four decades ago, however, the product was merely a thioamide-dipetide, which was formed in the absence of any mRNA. Since then, there has been no report on the ribosomal synthesis of peptides containing thioamide bonds. Here, we successfully demonstrated that the ribosome is capable in catalyzing the formation of a thioamide bond in an mRNA dependent fashion during peptide translation. Central to this achievement was the flexizyme technology that, for the very first time, allowed for the preparation of an amino(thio)acyl-tRNA, AlaS-tRNAGluE2. By reprogramming the genetic code in the FIT system, we synthesized peptide with a thioamide backbone. The chemical synthesis of peptides with one or more thioamide backbones has already been established; and the strategy presented here can allow for the generation of a ~10^12 membered library of peptides with one or more thioamide backbones via mRNA display platform. Therefore, in the future, a combination of mRNA display and chemical synthesis will lead to the discovery of macrocyclic thioamide-peptides with attractive biological and pharmacological properties.