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Chemical Synthesis of Proteins Using N-Sulfanylethylanilide Peptides, Based on N−S Acyl Transfer Chemistry

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Book cover Protein Ligation and Total Synthesis II

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 363))

Abstract

Native chemical ligation (NCL), which features the use of peptide thioesters, is among the most reliable ligation protocols in chemical protein synthesis. Thioesters have conventionally been synthesized using tert-butyloxycarbonyl (Boc)-based solid-phase peptide synthesis (SPPS); however, the increasing use of 9-fluorenylmethyloxycarbonyl (Fmoc) SPPS requires an efficient preparative protocol for thioesters which is fully compatible with Fmoc chemistry. We have addressed this issue by mimicking the naturally occurring thioester-forming step seen in intein-mediated protein splicing of the intein−extein system, using an appropriate chemical device to induce N−S acyl transfer reaction, avoiding the problems associated with Fmoc strategies. We have developed N-sulfanylethylanilide (SEAlide) peptides, which can be synthesized by standard Fmoc SPPS and converted to the corresponding thioesters through treatment under acidic conditions. Extensive examination of SEAlide peptides showed that the amide-type SEAlide peptides can be directly and efficiently involved in NCL via thioester species in the presence of phosphate salts, even under neutral conditions. The presence or absence of phosphate salts provided kinetically controllable chemoselectivity in NCL for SEAlide peptides. This allowed SEAlide peptides to be used in both one-pot/N−to−C-directed sequential NCL under kinetically controlled conditions, and the convergent coupling of large peptide fragments, which facilitated the chemical synthesis of proteins over about 100 residues. The use of SEAlide peptides, enabling sequential NCL operated under kinetically controlled conditions, and the convergent coupling, were used for the total chemical synthesis of a 162-residue monoglycosylated GM2-activator protein (GM2AP) analog.

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Abbreviations

Ac:

Acetyl

Acm:

Acetamidemethyl

Ar:

Aryl

Boc:

tert-Butoxycarbonyl

Bu:

Butyl

DMF:

Dimethylformamide

Fmoc:

9-Fluorenylmethyloxycarbonyl

GM2:

Ganglioside GM2

GM2AP:

GM2-activator protein

GM3:

Ganglioside GM3

Gn:

Guanidine

hANP:

Human atrial natriuretic peptide

HEPPS:

3-[4-(2-Hydroxyethyl)piperazin-1-yl]propane-1-sulfonic acid

HexA:

β-Hexosaminidase A

HSPro:

Sulfanylproline

KCL:

Kinetically controlled NCL

MBom:

4 Methoxybenzyloxymethyl

Me:

Methyl

MPAA:

(4-Carboxymethyl)thiophenol

NCL:

Native chemical ligation

OTf:

Trifluoromethanesulfonate

Ph:

Phenyl

rt:

Room temperature

SEAlide:

N-Acyl-N-sulfanylethylaniline

SPPS:

Solid-phase peptide synthesis

t-Bu:

tert-Butyl

TCEP:

Tris(2-carboxyethyl)phosphine (TCEP)

TFA:

Trifluoroacetic acid

Thz:

1,3-Thiazolidine-4-carbonyl

Tr:

Triphenylmethyl (trityl)

A (Ala):

Alanine

C (Cys):

Cysteine

D (Asp):

Aspartic acid

E (Glu):

Glutamic acid

F (Phe):

Phenylalanine

G (Gly):

Glycine

H (His):

Histidine

I (Ile):

Isoleucine

K (Lys):

Lysine

L (Leu):

Leucine

M (Met):

Methionine

N (Asn):

Asparagine

P (Pro):

Proline

Q (Gln):

Glutamine

R (Arg):

Arginine

S (Ser):

Serine

T (Thr):

Threonine

V (Val):

Valine

W (Trp):

Tryptophan

Y (Tyr):

Tyrosine

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  1. Institute of Health Biosciences and Graduate School of Pharmaceutical Sciences, Tokushima University, Shomachi, Tokushima, 770-8505, Japan

    Akira Otaka, Kohei Sato & Akira Shigenaga

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  1. Akira Otaka
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  2. Kohei Sato
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  3. Akira Shigenaga
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Correspondence to Akira Otaka .

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  1. Department of Chemistry, Tsinghua University, Beijing, China

    Lei Liu

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Otaka, A., Sato, K., Shigenaga, A. (2014). Chemical Synthesis of Proteins Using N-Sulfanylethylanilide Peptides, Based on N−S Acyl Transfer Chemistry. In: Liu, L. (eds) Protein Ligation and Total Synthesis II. Topics in Current Chemistry, vol 363. Springer, Cham. https://doi.org/10.1007/128_2014_586

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