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Peptide Thioester Formation via an Intramolecular N to S Acyl Shift for Peptide Ligation

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Protein Ligation and Total Synthesis I

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 362))

Abstract

In chemical protein synthesis, peptide building blocks are prepared by solid-phase peptide synthesis (SPPS), and then connected by chemical ligation methods. The peptide thioester is one of key building blocks used in chemical protein synthesis, and improvements in the Fmoc SPPS procedure for preparing such thioesters would be highly desirable. In this review we focus on a method for peptide thioester synthesis based on the use of an intramolecular N to S acyl shift reaction as a key reaction. Amide and thioester forms at the thiol-containing residue are in equilibrium as a result of a reversible intramolecular acyl shift, which is detectable by 13C NMR. The amide form is favored under neutral conditions, while the thioester predominates under acidic conditions. Thiol auxiliaries can be employed to facilitate the formation of a thioester from an amide via an intramolecular N–S acyl shift, and the peptide thioester is formed after intermolecular transthioesterification in the presence of excess amounts of thiols. Even under neutral conditions, thiol auxiliary-containing peptides can be ligated with a cysteinyl peptide via an intramolecular N–S acyl shift, followed by native chemical ligation (NCL) in a one-pot reaction. These procedures can be applied to the chemical synthesis of proteins which are post-translationally modified.

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Abbreviations

Acm:

Acetamidomethyl

Boc:

tert-Butoxycarbonyl

CPC:

Cysteinylprolylcysteine

CPE:

Cysteinylproline ester

DEAD:

Diethyl azodicarboxylate

DIEA:

N,N-Diisopropylethylamine

DIPCI:

N,N′-Diisopropylcarbodiimide

DKP:

Diketopiperazine

Dmmb:

4,5-Dimethoxy-2-mercaptobenzyl

DMSO:

Dimethyl sulfoxide

DTT:

Dithiothreitol

Fmoc:

9-Fluorenylmethoxycarbonyl

Gdn:

Guanidine

HBTU:

2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

HFBA:

Heptafluorobutyric acid

HOBt:

1-Hydroxybenzotriazole

HOObt:

3,4-Dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine

HOSu:

N-Hydroxysuccinimide

MAP:

Methionine aminopeptidase

MBHA:

4-Methylbenzhydrylamine

MESNa:

Sodium 2-mercaptoethanesulfonate

MPA:

3-Mercaptopropionic acid

NAC:

N-Alkyl cysteine

NCL:

Native chemical ligation

NMR:

Nuclear magnetic resonance

PDF:

Peptide deformylase

PURE system:

Protein synthesis using recombinant elements system

RP-HPLC:

Reversed-phase high performance liquid chromatography

SPPS:

Solid-phase peptide synthesis

t-Bu:

tert-Butyl

TCEP:

Tris(2-carboxyethyl)phosphine

TFA:

Trifluoroacetic acid

TFMSA:

Trifluoromethanesulfonic acid

Tle:

tert-Leucine

Trt:

Trityl

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Authors and Affiliations

  1. Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Toru Kawakami

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  1. Toru Kawakami
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Correspondence to Toru Kawakami .

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Editors and Affiliations

  1. Department of Chemistry, Tsinghua University, Bei**g, China

    Lei Liu

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Kawakami, T. (2014). Peptide Thioester Formation via an Intramolecular N to S Acyl Shift for Peptide Ligation. In: Liu, L. (eds) Protein Ligation and Total Synthesis I. Topics in Current Chemistry, vol 362. Springer, Cham. https://doi.org/10.1007/128_2014_575

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