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Vinylphosphonites for staudinger-induced chemoselective peptide cyclization and functionalization

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Item Type:Article
Title:Vinylphosphonites for staudinger-induced chemoselective peptide cyclization and functionalization
Creators Name:Kasper, M.A, Glanz, M., Oder, A., Schmieder, P., von Kries, J.P. and Hackenberger, C.P.R.
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.
Keywords:Protein Modification, Drug, Strategies, Stability, Chemistry
Source:Chemical Science
ISSN:2041-6520
Publisher:Royal Society of Chemistry
Volume:10
Number:25
Page Range:6322-6329
Date:7 July 2019
Official Publication:https://doi.org/10.1039/C9SC01345H
PubMed:View item in PubMed

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