Rapid access to Asp/Glu sidechain hydrazides as thioester precursors for peptide cyclization and glycosylation

Barnes, Natalie G.; Nyandoro, Kudakwashe; Jin, Hanzhang; Macmillan, Derek

doi:10.1039/d0cc07404g

Cited by 8 publications

(13 citation statements)

References 32 publications

(12 reference statements)

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“…13 In a related study, we examined the ability of an acyl transfer auxiliary to unite synthetic sugar derivatives, linked to an acyl transfer auxiliary, with synthetic peptide thioesters derived from the corresponding acyl hydrazides. 14 Our reactions were successful, but only when employing an additional methylene spacer (a C -glycoside) in the carbohydrate building block. Currently, proteins adorned with sidechain hydrazides of aspartic acid are not directly accessible using genetic means, although can be obtained from the corresponding genetically encoded benzyl ester.…”

Section: Resultsmentioning

confidence: 91%

“…Because the sidechain thioester is not stable to Fmoc-based SPPS, it was produced in situ from the corresponding hydrazide. 14 In contrast to the reaction with 16 , the ligation product was clearly observed as an inseparable pair of epimers, which returned to a single species, 25 , following cleavage of the racemic auxiliary (see ESI†). Confident that 15 and 19 served as reliable building blocks we turned to recombinant protein modification although, due to the ease of synthesis and use of 19 relative to 15 , only his building block was progressed.…”

Section: Resultsmentioning

confidence: 99%

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Investigation of acyl transfer auxiliary-assisted glycoconjugation for glycoprotein semi-synthesis

Nyandoro¹,

Lamb²,

et al. 2022

Org. Biomol. Chem.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Investigation of acyl transfer auxiliary-assisted glycoconjugation for glycoprotein semi-synthesis

Nyandoro¹,

Lamb²,

et al. 2022

Org. Biomol. Chem.

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“…Finally, peptide thioesters terminating at a C-terminal Asp, Glu, Asn, Gln or Lys residue, are prone to cyclize via nucleophilic attack at the acyl center by the C-terminal side-chain functionality. The cyclization reaction at Lys, Asn and Gln residues may be suppressed by performing the ligation at pH 6–7; however, it is challenging to prevent the cyclization at Asp and Glu residues without masking their carboxylate side chains ( Barnes et al, 2021 ).…”

Section: Selected Examples Of Using Thiolated and Selenylated Amino A...mentioning

confidence: 99%

Synthetic Thiol and Selenol Derived Amino Acids for Expanding the Scope of Chemical Protein Synthesis

et al. 2022

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Cells employ post-translational modifications (PTMs) as key mechanisms to expand proteome diversity beyond the inherent limitations of a concise genome. The ability to incorporate post-translationally modified amino acids into protein targets via chemical ligation of peptide fragments has enabled the access to homogeneous proteins bearing discrete PTM patterns and empowered functional elucidation of individual modification sites. Native chemical ligation (NCL) represents a powerful and robust means for convergent assembly of two homogeneous, unprotected peptides bearing an N-terminal cysteine residue and a C-terminal thioester, respectively. The subsequent discovery that protein cysteine residues can be chemoselectively desulfurized to alanine has ignited tremendous interest in preparing unnatural thiol-derived variants of proteogenic amino acids for chemical protein synthesis following the ligation-desulfurization logic. Recently, the 21st amino acid selenocysteine, together with other selenyl derivatives of amino acids, have been shown to facilitate ultrafast ligation with peptidyl selenoesters, while the advancement in deselenization chemistry has provided reliable bio-orthogonality to PTMs and other amino acids. The combination of these ligation techniques and desulfurization/deselenization chemistries has led to streamlined synthesis of multiple structurally-complex, post-translationally modified proteins. In this review, we aim to summarize the latest chemical synthesis of thiolated and selenylated amino-acid building blocks and exemplify their important roles in conquering challenging protein targets with distinct PTM patterns.

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“…[17] This method avoids the need for strong oxidizing conditions, enabling broader compatibility with common synthetic peptide functionalities, and has been widely adopted in a broad range of applications. [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] The increased use of C-terminal α-hydrazides in peptide chemistry creates a demand for robust synthetic tools for accessing these moieties. A number of methods have been published to allow access to C-terminal hydrazides on both synthetic [15,16,38] and expressed [15,39,40] peptides and proteins.…”

Section: Introductionmentioning

confidence: 99%

A shelf stable Fmoc hydrazine resin for the synthesis of peptide hydrazides

Bird

Dawson

2022

Peptide Science

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C‐terminal hydrazides are an important class of synthetic peptides with an ever expanding scope of applications, but their widespread application for chemical protein synthesis has been hampered due to the lack of stable resin linkers for synthesis of longer and more challenging peptide hydrazide fragments. We present a practical method for the regeneration, loading, and storage of trityl‐chloride resins for the production of hydrazide containing peptides, leveraging 9‐fluorenylmethyl carbazate. We show that these resins are extremely stable under several common resin storage conditions. The application of these resins to solid phase peptide synthesis (SPPS) is demonstrated through the synthesis of the 40‐mer GLP‐1R agonist peptide “P5”. These studies support the broad utility of Fmoc‐NHNH‐Trt resins for SPPS of C‐terminal hydrazide peptides.

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Rapid access to Asp/Glu sidechain hydrazides as thioester precursors for peptide cyclization and glycosylation

Abstract: We present a streamlined approach to sidechain acyl hydrazides of aspartic and glutamic acids – user friendly precursors to peptide macrocycles and glycopeptide analogues.

Cited by 8 publications

References 32 publications

Investigation of acyl transfer auxiliary-assisted glycoconjugation for glycoprotein semi-synthesis

Investigation of acyl transfer auxiliary-assisted glycoconjugation for glycoprotein semi-synthesis

Synthetic Thiol and Selenol Derived Amino Acids for Expanding the Scope of Chemical Protein Synthesis

A shelf stable Fmoc hydrazine resin for the synthesis of peptide hydrazides

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