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Angew Chem Int Ed Engl. 2019 Aug 19;58(34):11625-11630. doi: 10.1002/anie.201814715. Epub 2019 Apr 29.

Cysteine-Selective Phosphonamidate Electrophiles for Modular Protein Bioconjugations.

Author information

1
Chemical Biology Department, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
2
Department of Chemistry, Humboldt Universität zu Berlin, Brook-Taylor-Str. 2, 12489, Berlin, Germany.
3
Department of Biology II, and Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Großhadenerstr. 2, 82152, Martinsried, Germany.
4
Department of Biology, Technische Universität Darmstadt, Schnittspahnstrasse 10, 64287, Darmstadt, Germany.

Abstract

We describe a new technique in protein synthesis that extends the existing repertoire of methods for protein modification: A chemoselective reaction that induces reactivity for a subsequent bioconjugation. An azide-modified building block reacts first with an ethynylphosphonite through a Staudinger-phosphonite reaction (SPhR) to give an ethynylphosphonamidate. The resulting electron-deficient triple bond subsequently undergoes a cysteine-selective reaction with proteins or antibodies. We demonstrate that ethynylphosphonamidates display excellent cysteine-selective reactivity combined with superior stability of the thiol adducts, when compared to classical maleimide linkages. This turns our technique into a versatile and powerful tool for the facile construction of stable functional protein conjugates.

KEYWORDS:

bioconjugation; bioorganic chemistry; bioorthogonal chemistry; cysteine-selective modification; protein modification

PMID:
30828930
DOI:
10.1002/anie.201814715

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