Chemical Synthesis of Proteins with Base‐Labile Posttranslational Modifications Enabled by a Boc‐SPPS Based General Strategy Towards Peptide C‐Terminal Salicylaldehyde Esters

Chemical synthesis of proteins bearing base‐labile post‐translational modifications (PTMs) is a challenging task. For instance, O‐acetylation and S‐palmitoylation PTMs cannot survive Fmoc removal conditions during Fmoc‐solid phase peptide synthesis (SPPS). In this work, we developed a new Boc‐SPPS‐b...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2023-01, Vol.62 (1), p.e202214053-n/a
Main Authors: Ma, Wenjie, Wu, Hongxiang, Liu, Sha, Wei, Tongyao, Li, Xiang David, Liu, Han, Li, Xuechen
Format: Article
Language:English
Subjects:
Acetylation
Aldehydes
Amino acids
Base-Labile
Boc SPPS
Caveolin
Chemical Protein Synthesis
Chemical synthesis
Esters
Esters - chemistry
Histone H3
Histones
Hydrophobicity
Palmitoylation
Peptide synthesis
Peptides
Peptides - chemistry
Protein synthesis
Proteins
Pyruvic acid
Salicylaldehyde Ester
Solid phases
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Summary:Chemical synthesis of proteins bearing base‐labile post‐translational modifications (PTMs) is a challenging task. For instance, O‐acetylation and S‐palmitoylation PTMs cannot survive Fmoc removal conditions during Fmoc‐solid phase peptide synthesis (SPPS). In this work, we developed a new Boc‐SPPS‐based strategy for the synthesis of peptide C‐terminal salicylaldehyde (SAL) esters, which are the key reaction partner in Ser/Thr ligation and Cys/Pen ligation. The strategy utilized the semicarbazone‐modified aminomethyl (AM) resin, which could support the Boc‐SPPS and release the peptide SAL ester upon treatment with TFA/H2O and pyruvic acid. The non‐oxidative aldehyde regeneration was fully compatible with all the canonical amino acids. Armed with this strategy, we finished the syntheses of the O‐acetylated protein histone H3(S10ac, T22ac) and the hydrophobic S‐palmitoylated peptide derived from caveolin‐1. A Boc‐SPPS based method towards the synthesis of peptide C‐terminal salicylaldehyde esters compatible with all canonical amino acids was developed. The method could facilitate the synthesis of proteins bearing base‐labile post‐translational modifications, e.g., O‐acetylation and S‐palmitoylation.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202214053