Epimerization-free access to C-terminal cysteine peptide acids, carboxamides, secondary amides, and esters<i>via</i>complimentary strategies

Arbour, Christine A.; Kondasinghe, Thilini D.; Saraha, Hasina Y.; Vorlicek, Teanna L.; Stockdill, Jennifer L.

doi:10.1039/c7sc03553e

Cited by 17 publications

(13 citation statements)

References 76 publications

(45 reference statements)

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“…Therefore, a few representative alcoholic cosolvents were evaluated. We previously found that i -PrOH reacted more slowly than primary alcohols, 9 so we reasoned that it would minimize ester byproduct formation. Gratifyingly, in the presence of NaSPh, these conditions reduced byproduct formation to 6% of the ester ( 15c ), which was indeed readily separated from the elongated acid LYRAGLRAYP ( 15a , entry 5).…”

Section: Resultsmentioning

confidence: 99%

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Sequence Diversification by Divergent C-Terminal Elongation of Peptides

2018

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Sequence diversification at the C terminus is traditionally limited by significant epimerization of the C-terminal residue during its activation toward nucleophilic attack, thus mandating repetition of the peptide synthesis for each targeted variation. Here, we accomplish divergent C-terminal elongation of a single peptide substrate with concomitant resin cleavage via displacement of an N-acyl urea moiety. Sterically hindered amino acids such as Ile and Pro are well-tolerated in this approach, which proceeds reasonable conversion and no detectable epimerization of the starting peptide's C-terminal amino acid.

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Section: Resultsmentioning

confidence: 99%

“…6,8 During this work, we found that the C-terminal residue is not epimerized during the modification reaction, even for sensitive residues such as His or Cys. 9 Therefore, we viewed this approach as ideal for backbone sequence diversification at the C terminus.…”

Section: Introductionmentioning

confidence: 99%

Sequence Diversification by Divergent C-Terminal Elongation of Peptides

2018

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“…The Nbz/MeNbz technology has been successfully implemented in the preparation of glycoproteins-, phosphoproteins-, lipoproteins-, and cyclic proteins [32,[35][36][37][38][39][40][41][42][43][44]. In addition, this cleavable Nbz/MeNbz linker can undergo the attack of other nucleophiles rendering C-terminal modified peptides selectively labeled with different functionalities such as N-alkyl amides, esters, or cyclic peptides [45][46][47].…”

Section: N-acylurea Peptides As Thioester Surrogatesmentioning

confidence: 99%

Native Chemical Ligation via N-Acylurea Thioester Surrogates Obtained by Fmoc Solid-Phase Peptide Synthesis

Palà-Pujadas

Blanco‐Canosa

2020

Expressed Protein Ligation

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Native chemical ligation (NCL) enables the direct chemical synthesis and semisynthesis of proteins of different sizes and compositions, streamlining the access to proteins containing posttranslational modifications (PTMs). NCL assembles peptide fragments through the chemoselective reaction of a C-terminal α-thioester peptide, prepared either by chemical synthesis or via intein-splicing technology, and a recombinant or synthetic peptide containing an N-terminal Cys. Whereas the generation of C-terminal α-thioester proteins can be achieved via the recombinant fusion of the sequence of interest to an intein domain, chemical methods can also be used for synthetically accessible proteins. The use of Fmoc -solid-phase peptide synthesis (Fmoc-SPPS) to obtain α-thioester peptides requires the development of novel strategies to overcome the lability of the thioester bond toward piperidine Fmoc-removal conditions. These new synthetic methods enable the easy introduction of PTMs in the thioester fragment. In this chapter, we describe an approach for the synthesis and use of C-terminal α-N-acylbenzimidazolinone (Nbz) and α-N-acyl-N′'-methylbenzimidazolinone (MeNbz) peptides in NCL. Following stepwise peptide elongation, acylation with p-nitrophenylchloroformate and cyclization affords the Nbz/MeNbz peptides. The optimization of the coupling conditions allows the chemoselective incorporation of the C-terminal amino acid (aa) on the 3,4diaminobenzoyl (Dbz) and prevents undesired diacylations of the resulting oaminoanilide. Following synthesis, these Nbz/MeNbz peptides undergo NCL straightforwardly at neutral pH catalyzed by the presence of arylthiols. Herein, we apply the Nbz technology solid phase synthesis, NCL-mediated cyclization and folding of the heterodimeric RTD-1 defensin, an antimicrobial peptide isolated from the rhesus macaque leukocytes.

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“…To solve the problem of epimerization during carboxylate activation, many research groups have reported the use of various “linkers”, commonly Dbz, MeDbz, hydrazine, nitroindoline, etc . (Scheme C).…”

Section: Native Chemical Ligation (Ncl)mentioning

confidence: 99%

Chemical Protein Synthesis by Native Chemical Ligation and Variations Thereof

et al. 2019

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For a long time, the total synthesis of proteins was considered as a “mission impossible” because of the tedious and complex synthetic steps and demanding purification processes. However, with the development of modern synthetic methodologies, many protein syntheses have now been reported. More importantly, through chemical synthesis, desired modifications can be installed to target proteins precisely, which is a major advantage over traditional bio‐synthesis approaches. This review summarizes the techniques developed for protein assembly, including native chemical ligation, Se‐mediated ligation, and a range of other ligation methods. A few synthetic examples, whereby synthetic proteins with desired modifications have been utilized for related biological research, are also included. We believe that chemical synthesis can provide alternative pathways to solve problems that have hitherto proved insurmountable by traditional biological approaches.

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Epimerization-free access to C-terminal cysteine peptide acids, carboxamides, secondary amides, and estersviacomplimentary strategies

Abstract: We present a convenient method for the diversification of peptides bearing cysteine at the C-terminus that proceeds to form a variety of carboxylic acid, carboxamide, 2° amide, and ester terminated peptides without any detectable epimerization of the α-stereocenter.

Cited by 17 publications

References 76 publications

Sequence Diversification by Divergent C-Terminal Elongation of Peptides

Sequence Diversification by Divergent C-Terminal Elongation of Peptides

Native Chemical Ligation via N-Acylurea Thioester Surrogates Obtained by Fmoc Solid-Phase Peptide Synthesis

Chemical Protein Synthesis by Native Chemical Ligation and Variations Thereof

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