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Issue 23, 2019
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Cysteinylprolyl imide (CPI) peptide: a highly reactive and easily accessible crypto-thioester for chemical protein synthesis

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Abstract

Native chemical ligation (NCL) between the C-terminal peptide thioester and the N-terminal cysteinyl-peptide revolutionized the field of chemical protein synthesis. The difficulty of direct synthesis of the peptide thioester in the Fmoc method has prompted the development of crypto-thioesters that can be efficiently converted into thioesters. Cysteinylprolyl ester (CPE), which is an NS acyl shift-driven crypto-thioester that relies on an intramolecular ON acyl shift to displace the amide-thioester equilibrium, enabled trans-thioesterification and subsequent NCL in one pot. However, the utility of CPE is limited because of the moderate thioesterification rates and the synthetic complexity introduced by the ester group. Herein, we develop a new crypto-thioester, cysteinylprolyl imide (CPI), which replaces the alcohol leaving group of CPE with other leaving groups such as benzimidazolidinone, oxazolidinone, and pyrrolidinone. CPI peptides were efficiently synthesized by using standard Fmoc solid-phase peptide synthesis (SPPS) and subsequent on-resin imide formation. Screening of the several imide structures indicated that methyloxazolidinone-t-leucine (MeOxd-Tle) showed faster conversion into thioester and higher stability against hydrolysis under NCL conditions. Finally, by using CPMeOxd-Tle peptides, we demonstrated the chemical synthesis of affibody via N-to-C sequential, three-segment ligation and histone H2A.Z via convergent four-segment ligation. This facile and straightforward method is expected to be broadly applicable to chemical protein synthesis.

Graphical abstract: Cysteinylprolyl imide (CPI) peptide: a highly reactive and easily accessible crypto-thioester for chemical protein synthesis

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Supplementary files

Article information


Submitted
06 Feb 2019
Accepted
09 May 2019
First published
09 May 2019

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2019,10, 5967-5975
Article type
Edge Article

Cysteinylprolyl imide (CPI) peptide: a highly reactive and easily accessible crypto-thioester for chemical protein synthesis

M. Yanase, K. Nakatsu, C. J. Cardos, Y. Konda, G. Hayashi and A. Okamoto, Chem. Sci., 2019, 10, 5967
DOI: 10.1039/C9SC00646J

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material.

Reproduced material should be attributed as follows:

  • For reproduction of material from NJC:
    [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
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    [Original citation] - Published by the PCCP Owner Societies.
  • For reproduction of material from PPS:
    [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
  • For reproduction of material from all other RSC journals:
    [Original citation] - Published by The Royal Society of Chemistry.

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