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ACS Chem Biol. 2008 Apr 18;3(4):241-9. doi: 10.1021/cb800010p. Epub 2008 Mar 14.

Ribosomal synthesis of peptidase-resistant peptides closed by a nonreducible inter-side-chain bond.

Author information

1
Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1, Komaba, Meguro, Tokyo, 153-8904, Japan.

Abstract

Here we report a new enabling technology for the synthesis of peptidase-resistant cyclic peptides by means of genetic code reprogramming involving the flexizyme (a tRNA acylation ribozyme) and PURE (a reconstituted cell-free translation) systems. In this work, we have developed a new nonproteinogenic amino acid bearing a chloroacetyl group in the side chain, which forms a physiologically stable thioether bond by intramolecular reaction with the sulfhydryl group of a Cys residue in the peptide chain upon translation. Significantly, this chemistry takes place spontaneously in situ of the translation solution, giving the corresponding cyclic peptides independent of ring sizes. We have used this method to convert human urotensin II, known as a potent vasoconstrictor, to its analogue containing a thioether bond, showing that this new analogue retains biological activity. Moreover, this peptide exhibits remarkable resistance against peptidases under reducing conditions. Thus, this technology offers a new means to accelerate the discovery of therapeutic peptidic drugs.

PMID:
18338852
DOI:
10.1021/cb800010p
[Indexed for MEDLINE]

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