Reprogramming the translation initiation for the synthesis of physiologically stable cyclic peptides

ACS Chemical Biology
Yuki GotoHiroaki Suga

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.

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Citations

Dec 1, 2010·Pharmaceutical Research·Luis BerradeJulio A Camarero
Jun 30, 2011·Accounts of Chemical Research·Jumpei MorimotoHiroaki Suga
Nov 17, 2009·Nature Chemical Biology·Takashi KawakamiHiroaki Suga
Jun 4, 2011·Nature Protocols·Yuki GotoHiroaki Suga
Mar 24, 2009·Nature Structural & Molecular Biology·Hiroshi MurakamiHiroaki Suga
Jul 8, 2011·Chemical Communications : Chem Comm·Toshimasa HamamotoMasumi Taki
Jul 19, 2011·Chemical Communications : Chem Comm·Takayuki KatohHiroaki Suga
Sep 21, 2011·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Hiroaki SugaNaohiro Terasaka
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Mar 25, 2015·International Journal of Molecular Sciences·Naohiro TerasakaHiroaki Suga
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Mar 20, 2013·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kenichiro ItoHiroaki Suga
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