Ribosomal synthesis of bicyclic peptides via two orthogonal inter-side-chain reactions.
Here we report a new methodology for the synthesis of bicyclic peptides by using a reconstituted cell-free translation system under the reprogrammed genetic code. Cysteine (Cys) and three different nonproteinogenic amino acids, Cab, Aha, and Pgl, were simultaneously incorporated into a peptide chain. The first cyclization occurred between the chloroacetyl group of Cab and the sulfhydryl group in Cys in situ of translation, and the second cyclization on the side chains of Aha-Pgl via Cu(I)-catalyzed azide-alkyne cycloaddition was performed. This offers us a powerful means of mRNA-programmed synthesis of various peptides with uniform bicyclic scaffolds.
Sako
Yusuke
Y
Research Center for Advanced Science and Technology, The University of Tokyo, Komaba, Meguro, Tokyo 153-8904, Japan.
Morimoto
Jumpei
J
Murakami
Hiroshi
H
Suga
Hiroaki
H
D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000480:Alkynes / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D000613:Aminobutyrates / Q000737:chemistry / Q000378:metabolism; D003062:Codon; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D010456:Peptides, Cyclic / Q000096:biosynthesis / Q000138:chemical synthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013698:Templates, Genetic
D000480:Alkynes; D000596:Amino Acids; D000613:Aminobutyrates; D003062:Codon; D010456:Peptides, Cyclic; D012333:RNA, Messenger; C506098:azidohomoalanine; C009055:propargylglycine; D003545:Cysteine; D000409:Alanine; D005998:Glycine