One-Pot Cyclization and Cleavage of Peptides with N-Terminal Cysteine via the N,S-Acyl Shift of the N-2-[Thioethyl]glycine Residue

Wierzbicka, Magdalena; Waliczek, Mateusz; Dziadecka, Anna; Stefanowicz, Piotr

doi:10.1021/acs.joc.1c01045

Cited by 5 publications

(2 citation statements)

References 40 publications

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“…The presence of N-Me-L-Phe in xylapeptide A residues also can facilitate cyclization because it can direct the cisamide conformation thereby allowing the reverse-turn formation of peptide cyclization [13]. The cyclization was performed in solution-phase at a dilute concentration of 10 À3 to 10 À4 M to suppress the potency of cyclodimerization [14,15]. HBTU was selected as a coupling reagent to reduce coupling reactivity to suppress racemization during cyclization [16].…”

Section: Introductionmentioning

confidence: 99%

Total synthesis and antimicrobial evaluation of xylapeptide A

Muchlis

Kurnia

Maharani

et al. 2022

Journal of Heterocyclic Chem

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Xylapeptide A is a cyclopentapeptide, [cyclo-D-Ala-L-Val-N-Me-L-Phe-L-Pip-L-Leu], first isolated from Xylaria sp. Â Sophora tonkinensis, together with its analogue, xylapeptide B, which differ by only one residue, proline in xylapeptide B is replaced by pipecolinic acid (Pip) in xylapeptide A. Both xylapeptides A and B possess antimicrobial properties against several bacteria and fungi. Herein, we describe the first total synthesis and antimicrobial evaluation of xylapeptide A containing two non-proteinogenic residues, N-Me-phenylalanine and pipecolinic acid. The synthesis of xylapeptide A was achieved by a combination of solid-and solution-phase methods that were applied for the synthesis of xylapeptide B. Interestingly, the cyclization of linear xylapeptide A was more straightforward yielding 22% compared to 8.9% for xylapeptide B, suggesting that the presence of pipecolinic acid in the linear precursor affected the cyclization process. NMR analysis of synthetic xylapeptide A revealed that the chemical shifts of all protons and carbons of xylapeptide A are highly similar to the natural product. The synthetic xylapeptide A, together with xylapeptide B, were evaluated for their antimicrobial properties, showing that synthetic xylapeptide A has moderate antimicrobial activity and better antimicrobial properties compared to synthetic xylapeptide B. The presence of pipecolinic acid in xylapeptide A is an important requirement for antimicrobial activity.

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Section: Introductionmentioning

confidence: 99%

Total synthesis and antimicrobial evaluation of xylapeptide A

Muchlis

Kurnia

Maharani

et al. 2022

Journal of Heterocyclic Chem

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“…22 In our approach, two glycine residues, placed in positions i and i + 1, were replaced by N -(2-thioethyl)glycine derivatives resulting in the leu-enkephalin peptoid ( 1 ) which was further cyclized through reactive –SH groups. The analog 1, which was synthesized based on the modified protocol developed by our group, 23 was subjected to a cyclization reaction using two different reagents: hexafluorobenzene (Scheme 1a) and the trithiocyanuric acid derivative (Scheme 1b). As reported previously, cyclization through SH groups resulted in promising cyclic opioid peptides – DPDPE (( d -Pen2, d -Pen5)-enkephalin) in which the Gly 2 and Leu 5 residues were replaced by the unnatural amino acid – Pen (penicillamine).…”

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confidence: 99%

Stapling of leu-enkephalin analogs with bifunctional reagents for prolonged analgesic activity

Kijewska,

Wołczański,

Kosson

et al. 2024

Chem. Commun.

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Selective Activation of Peptide‐Thioester Precursors for Templated Native Chemical Ligations

Spaltenstein,

Giesler,

Scherer

et al. 2024

Angewandte Chemie

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Chemical protein synthesis enables access to proteins that would otherwise be difficult or impossible to obtain with traditional means such as recombinant expression. Chemoselective ligations provide the ability to join peptide segments prepared by solid‐phase peptide synthesis. While native chemical ligation (NCL) is widely used, it is limited by the need for C‐terminal thioesters with suitable reaction kinetics, properly placed native Cys or thiolated derivatives, and peptide segment solubility at low mM concentrations. Moreover, repetitive purifications to isolate ligated products are often yield‐sapping, hampering efficiency and progress. In this work, we demonstrate the use of Controlled Activation of Peptides for Templated NCL (CAPTN). This traceless multi‐segment templated NCL approach permits the one‐pot synthesis of proteins by harnessing selective thioester activation and orthogonal conjugation chemistries to favor formation of full‐length ligated product while minimizing side reactions. Importantly, CAPTN provides kinetic enhancements allowing ligations at sterically hindered junctions and low peptide concentrations. Additionally, this one‐pot approach removes the need for intermediate purification. We report the synthesis of two E.coli ribosomal subunits S16 and S17 enabled by the chemical tools described herein. We anticipate that CAPTN will expedite the synthesis of valuable proteins and expand on templated approaches for chemical protein synthesis.

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One-Pot Cyclization and Cleavage of Peptides with N-Terminal Cysteine via the N,S-Acyl Shift of the N-2-[Thioethyl]glycine Residue

Cited by 5 publications

References 40 publications

Total synthesis and antimicrobial evaluation of xylapeptide A

Total synthesis and antimicrobial evaluation of xylapeptide A

Stapling of leu-enkephalin analogs with bifunctional reagents for prolonged analgesic activity

Selective Activation of Peptide‐Thioester Precursors for Templated Native Chemical Ligations

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