Efficient Peptide Alkyl Thioester Synthesis from Advanced Thiols and Peptide Hydrazides

Di Adamo, Julie; Ollivier, Nathalie; Diemer, Vincent; Melnyk, Oleg

Document type :

Compte-rendu et recension critique d'ouvrage

DOI :

10.1021/acs.joc.4c01251

Permalink :

http://hdl.handle.net/20.500.12210/118202

Title :

Efficient Peptide Alkyl Thioester Synthesis from Advanced Thiols and Peptide Hydrazides

Author(s) :

Di Adamo, Julie [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Université de Lille
Ollivier, Nathalie [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Institut Pasteur de Lille
Diemer, Vincent [Auteur]

Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Melnyk, Oleg [Auteur]

Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]

Journal title :

Journal of Organic Chemistry

Pages :

13719-13724

Publisher :

American Chemical Society

Publication date :

2024-05-20

ISSN :

0022-3263

HAL domain(s) :

Chimie

English abstract : [en]

<div><p>Peptide alkyl thioesters are versatile reagents in various synthetic applications, commonly generated from peptide hydrazides and thiols. However, a notable limitation is the need for a substantial excess of the ...
Show more ><div><p>Peptide alkyl thioesters are versatile reagents in various synthetic applications, commonly generated from peptide hydrazides and thiols. However, a notable limitation is the need for a substantial excess of the thiol reagent, restricting usage to simple thiols. Here, we introduce an adapted procedure that significantly enhances thioester production with just a minimal thiol excess, facilitating the use of advanced thiol nucleophiles.</p><p>Alkyl thioester functionality is characterized by a low hydrolysis rate in neutral aqueous media, minimal propensity for racemization or epimerization, and a strong reactivity towards S-nucleophiles like thiols. 1 These properties make alkyl thioesters particularly attractive in diverse applications such as protein semi or total synthesis, 2-6 the study of protein folding, 7 the design of dynamic combinatorial libraries 8-9 and the production of organic polymers. 10 In particular, peptide alkyl thioesters are popular reagents for the chemical synthesis of proteins using the native chemical ligation (NCL), which consists in reacting a C-terminal peptidyl thioester with an N-terminal cysteinyl (Cys) peptide to produce a larger peptide through the chemoselective formation of a peptide bond to cysteine. Logically, many works were devoted to their synthesis using solid phase, liquid phase or hybrid solid phase-liquid phase approaches. 2 The widespread adoption of the 9-fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis method by the peptide community has favored the development of the hybrid solid phase-liquid phase approach. This tendency is due to the incompatibility of the thioester functionality with the repeated piperidine treatments used to remove the Fmoc group during the elongation of the peptide sequence on the solid support. Practically, peptide thioesters are frequently prepared in aqueous solution from unprotected precursors produced by conventional Fmoc SPPS. 11 Amide and hydrazide precursors are appreciated for their excellent stability and ease of synthesis. 12-16 In both cases, the thioester group is formed through an activation-displacement mechanism that requires a large excess of an alkylthiol to achieve good yields. Although highly efficient and popular, these methods are restricted to the use of simple and cheap thiols such as sodium 2-ethanesulfonate (MESNa 17 ), 3-mercaptopropionic acid (MPA 12-13 ) or 3-mercaptopropiosulfonate (MPSNa 18 ) owing to the excess of thiol required. Peptide thioesters derived from advanced thiols require the setup of special protocols. For example, peptide thioesters equipped with an oligoarginine tag in the thiol arm are accessible through Boc SPPS. 19 The production of peptide alkyl thioesters from advanced alkyl thiols is of high interest for modulating peptide segment solubility 19 or thioester group chemical 20 or biochemical reactivity. 21 We show here that one of the most popular method for peptide thioester synthesis, the peptide hydrazide method designed by Liu's group, 15 can be adapted to access various types of alkyl thioesters using nearly stoichiometric quantities of the alkyl thiol nucleophile by exploiting an hallmark of the thiol-thioester exchange process, i.e., its reversibility.</p></div>Show less >

Language :

Anglais

Popular science :

Non

Collections :

Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017

Source :

Harvested from HAL

Submission date :

2024-10-26T02:09:51Z

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