Issue 25, 2019

Vinylphosphonites for Staudinger-induced chemoselective peptide cyclization and functionalization

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

Supplementary files

Article information

Article type
Edge Article
Submitted
19 Mar 2019
Accepted
10 May 2019
First published
16 May 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2019,10, 6322-6329

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, 10, 6322 DOI: 10.1039/C9SC01345H

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