Facile Synthesis of Peptidyl Salicylaldehyde Esters and Its Use in Cyclic Peptide Synthesis

Zhao, Junfeng; Zhang, Xiaohong; Ding, Yingjie; Ming, Yang; Bi, Xiaobao; Liu, Chuan‐Fa

doi:10.1021/ol402279h

Cited by 31 publications

(26 citation statements)

References 40 publications

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“…In addition, STL-mediated peptide cyclization has been used to synthesize daptomycin and other cyclic peptides of various sizes (Lam et al, 2013; Wong et al, 2013a,b; Zhao et al, 2013). More recently, STL has been used in the form of expression protein ligation, producing a RNase-peptiod conjugate (Levine et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Realizing serine/threonine ligation: scope and limitations and mechanistic implication thereof

Wong

Lam

et al. 2014

Front. Chem.

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Serine/Threonine ligation (STL) has emerged as an alternative tool for protein chemical synthesis, bioconjugations as well as macrocyclization of peptides of various sizes. Owning to the high abundance of Ser/Thr residues in natural peptides and proteins, STL is expected to find a wide range of applications in chemical biology research. Herein, we have fully investigated the compatibility of the STL strategy for X-Ser/Thr ligation sites, where X is any of the 20 naturally occurring amino acids. Our studies have shown that 17 amino acids are suitable for ligation, while Asp, Glu, and Lys are not compatible. Among the working 17 C-terminal amino acids, the retarded reaction resulted from the bulky β-branched amino acid (Thr, Val, and Ile) is not seen under the current ligation condition. We have also investigated the chemoselectivity involving the amino group of the internal lysine which may compete with the N-terminal Ser/Thr for reaction with the C-terminal salicylaldehyde (SAL) ester aldehyde group. The result suggested that the free internal amino group does not adversely slow down the ligation rate.

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Section: Introductionmentioning

confidence: 99%

Realizing serine/threonine ligation: scope and limitations and mechanistic implication thereof

Wong

Lam

et al. 2014

Front. Chem.

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“…However, an additional peak at slightly higher retention time appeared in the HPLC profile, whose identity could not be assessed by mass spectrometry. Owing to the fact that the presence of a tryptophan residue in the sequence excluded the use of any protocol involving aldehyde generation by means of post-SPPS oxidative processes, 68 the esterification in solution was chosen. The peptide was assembled on the H-Thr(tBu)-chlorotrityl resin (0.73 mmol/g) and released from the solid support under mildly acidic conditions (Scheme 4).…”

Section: Synthesis Of [Met(o)-432]-igg1-fc 398-450 (1) By Chemoselementioning

confidence: 99%

An explorative study towards the chemical synthesis of the immunoglobulin G1 Fc CH3 domain

Grassi

Roschger

Stanojlović

et al. 2018

Journal of Peptide Science

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Monoclonal antibodies, fusion proteins including the immunoglobulin fragment c (Ig Fc) CH2‐CH3 domains, and engineered antibodies are prominent representatives of an important class of drugs and drug candidates, which are referred to as biotherapeutics or biopharmaceuticals. These recombinant proteins are highly heterogeneous due to their glycosylation pattern. In addition, enzyme‐independent reactions, like deamidation, dehydration, and oxidation of sensitive side chains, may contribute to their heterogeneity in a minor amount. To investigate the biological impact of a spontaneous chemical modification, especially if found to be recurrent in a biotherapeutic, it would be necessary to reproduce it in a homogeneous manner. Herein, we undertook an explorative study towards the chemical synthesis of the IgG1 Fc CH3 domain, which has been shown to undergo spontaneous changes like succinimide formation and methionine oxidation. We used Fmoc‐solid‐phase peptide synthesis (SPPS) and native chemical ligation (NCL) to test the accessibility of large fragments of the IgG1 Fc CH3 domain. In general, the incorporation of pseudoproline dipeptides improved the quality of the crude peptide precursors; however, sequences larger than 44 residues could not be achieved by standard stepwise elongation with Fmoc‐SPPS. In contrast, the application of NCL with cysteine residues, which were either native or introduced ad hoc, allowed the assembly of the C‐terminal IgG1 Fc CH3 sequence 371 to 450. The syntheses reported here show advantages and limitations of the chemical approaches chosen for the preparation of the synthetic IgG1 Fc CH3 domain and will guide future plans towards the synthesis of both the native and selectively modified full‐length domain.

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“…This strategy provides a reliable approach to the Fmoc chemistry solid phase synthesis of peptide SAL esters (Scheme 2a,b). chain was first cleaved from the resin with either TFMSA/ TFA or HF, followed by in-solution ozonolysis to generate the peptide SAL esters [34 ]. It is noted that Cys, Met and Trp are incompatible with this method.…”

Section: Synthesis Of the Requisite Peptide Sal Estermentioning

confidence: 99%

“…Various cyclic peptides of sizes from 4 to 9 amino acids have been successfully prepared by way of serine/threonine ligation-mediated peptide cyclization [33 ,34 ]. As such, several natural bioactive cyclic peptides have been synthesized, including cyclomontanin B [38], yunnanin C [29], mahafacyclin B [34 ] and daptomycin [39] (Scheme 4). The cyclization proceeded smoothly, even in the presence of the unprotected lysine residue.…”

Section: Synthesis Of the Requisite Peptide Sal Estermentioning

confidence: 99%

Serine/threonine ligation for the chemical synthesis of proteins

Lee

2014

Current Opinion in Chemical Biology

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Facile Synthesis of Peptidyl Salicylaldehyde Esters and Its Use in Cyclic Peptide Synthesis

Abstract: An efficient solid phase synthetic protocol for salicylaldehyde ester peptides is reported. With a Ser or Thr at the N-terminus, these salicylaldehyde ester peptides can be easily converted to Ser/Thr containing cyclic peptides.

Cited by 31 publications

References 40 publications

Realizing serine/threonine ligation: scope and limitations and mechanistic implication thereof

Realizing serine/threonine ligation: scope and limitations and mechanistic implication thereof

An explorative study towards the chemical synthesis of the immunoglobulin G1 Fc CH3 domain

Serine/threonine ligation for the chemical synthesis of proteins

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