title: Reprogramming the translation initiation for the synthesis of physiologically stable cyclic peptides.
abstract: The initiation codon dictates that the translation initiation event exclusively begins with methionine. We report here a new technology to reprogram the initiation event, where various amino acids and those bearing N (alpha)-acyl groups can be used as an initiator for peptide synthesis. The technology is built upon the concept of genetic code reprogramming, where methionine is depleted from the translation system and the initiation codon is reassigned to the desired amino acid. We have applied this technology to the synthesis of an antitumor cyclic peptide, G7-18NATE, closed by a physiologically stable bond, and it is also extended to the custom synthesis of its analogues with various ring sizes. Significantly, cyclization occurs spontaneously upon translation of the precursor linear peptides. To demonstrate the practicality of this methodology, we also prepared a small cyclic peptide library designated by 160 distinct mRNAs. Thus, this technology offers a new means to prepare a wide array of in vivo compatible cyclic peptide libraries for the discovery of peptidic drug candidates against various therapeutic targets.
authors.affiliation: Research Center for Advanced Science and Technology, Graduate School of Engineering, The University of Tokyo, 4-6-1, Komaba, Meguro, Tokyo, 153-8904, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Goto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohta
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sako
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamagishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Murakami
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suga
mesh_terms: D049148:Aminoacylation; D018387:Codon, Initiator; D003500:Cyclization; D015394:Molecular Structure; D010442:Peptide Chain Initiation, Translational; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D012346:RNA, Transfer, Amino Acyl / Q000737:chemistry* / Q000378:metabolism; D012358:RNA, Transfer, Met / Q000737:chemistry / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D046249:Transfer RNA Aminoacylation
chemical_list: D018387:Codon, Initiator; C509376:G7-18NATE; D019151:Peptide Library; D010456:Peptides, Cyclic; D012346:RNA, Transfer, Amino Acyl; D012358:RNA, Transfer, Met