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Kasper, Marc-Andre; Glanz, Maria; Stengl, Andreas; Penkert, Martin; Klenk, Simon; Sauer, Tom; Schumacher, Dominik; Helma, Jonas; Krause, Eberhard; Cardoso, M. Cristina; Leonhardt, Heinrich; Hackenberger, Christian P. R. (2019): Cysteine-Selective Phosphonamidate Electrophiles for Modular Protein Bioconjugations. In: Angewandte Chemie-International Edition, Vol. 58, No. 34: pp. 11625-11630
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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.