Oxime/Hydrazone Conjugation at Histidine: Late-Stage Functionalization Approach of Unprotected Peptides.
Bio-conjugation
Late-stage functionalization
Peptide diversification
Radical chemistry
Journal
Methods in molecular biology (Clifton, N.J.)
ISSN: 1940-6029
Titre abrégé: Methods Mol Biol
Pays: United States
ID NLM: 9214969
Informations de publication
Date de publication:
2021
2021
Historique:
entrez:
13
8
2021
pubmed:
14
8
2021
medline:
15
1
2022
Statut:
ppublish
Résumé
Synthetic molecular probes have recently been in focus for their potential use in target deconvolution, target engagement studies, and imaging. With the field expanding, new strategies to develop such tools are in high demand. While traditional conjugation techniques relying on inherently nucleophilic amino acids such as cysteine (Cys) and lysine (Lys) or pre-incorporated non-natural amino acids are still heavily used, novel methodologies for the direct and site-selective modification of peptides are attracting increasing attention. Of particular interest are Late-Stage Functionalization (LSF) approaches based on radical chemistry as they afford mild and biocompatible alternatives to transition-metal catalysis. A recent synthetic method, which leverages the unique reactivity of histidine (His), has proven to be a promising new strategy for LSF and site-selective conjugation of unprotected peptides. In this chapter, detailed step-by-step protocols depicting the C2-alkylation of His-containing peptides, the unveiling of a ketone as handle for hydrazone conjugation, and its use to site-selectively introduce a fluorophore at this residue are discussed. In addition to its application toward the synthesis of molecular probes, this methodology can be employed in peptide-based drug discovery programs, offering the possibility to rapidly explore the chemical space surrounding peptide hits. Finally, this strategy is also amenable to the preparation of novel peptide-ASO/small molecule drug conjugates.
Identifiants
pubmed: 34386948
doi: 10.1007/978-1-0716-1617-8_4
doi:
Substances chimiques
Amino Acids
0
Hydrazones
0
Molecular Probes
0
Oximes
0
Peptides
0
Histidine
4QD397987E
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
35-48Informations de copyright
© 2021. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.
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