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

Chemical Science
Masafumi YanaseAkimitsu Okamoto

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 N-S acyl shift-driven crypto-thioester that relies on an intramolecular O-N 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 again...Continue Reading

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Citations

Oct 10, 2020·Organic & Biomolecular Chemistry·Skander A Abboud, Vincent Aucagne
May 31, 2020·Current Opinion in Chemical Biology·Koki NakatsuAkimitsu Okamoto
Nov 20, 2020·Journal of the American Chemical Society·Yi TanXuechen Li
Dec 4, 2019·The Journal of Organic Chemistry·Yuya Asahina, Hironobu Hojo

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Methods Mentioned

BETA
Size-exclusion chromatography

Software Mentioned

ACD Labs

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