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Vinylphosphonites for Staudinger-induced chemoselective peptide cyclization and functionalization

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Abstract

In this paper, we introduce vinylphosphonites for chemoselective Staudinger-phosphonite reactions (SPhR) with azides to form vinylphosphonamidates for the subsequent modification of cysteine residues in peptides and proteins. An electron-rich alkene is turned into an electron-deficient vinylphosphonamidate, thereby inducing electrophilic reactivity for a following thiol addition. We show that by varying the phosphonamidate ester substituent we can fine-tune the reactivity of the thiol addition and even control the functional properties of the final conjugate. Furthermore, we observed a drastic increase in thiol addition efficiency when the SPhR is carried out in the presence of a thiol substrate in a one-pot reaction. Hence, we utilize vinylphosphonites for the chemoselective intramolecular cyclization of peptides carrying an azide-containing amino acid and a cysteine in high yields. Our concept was demonstrated for the stapling of a cell-permeable peptidic inhibitor for protein–protein interaction (PPI) between BCL9 and beta-catenin, which is known to create a transcription factor complex playing a role in embryonic development and cancer origin, and for macrocyclization of cell-penetrating peptides (CPPs) to enhance the cellular uptake of proteins.

Graphical abstract: Vinylphosphonites for Staudinger-induced chemoselective peptide cyclization and functionalization

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Publication details

The article was received on 19 Mar 2019, accepted on 10 May 2019 and first published on 16 May 2019


Article type: Edge Article
DOI: 10.1039/C9SC01345H
Chem. Sci., 2019, Advance Article
  • Open access: Creative Commons BY-NC license
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    Vinylphosphonites for Staudinger-induced chemoselective peptide cyclization and functionalization

    M. Kasper, M. Glanz, A. Oder, P. Schmieder, J. P. von Kries and C. P. R. Hackenberger, Chem. Sci., 2019, Advance Article , DOI: 10.1039/C9SC01345H

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