Cysteine‐selective phosphonamidate electrophiles for modular protein bioconjugations

Angewandte Chemie International Edition,
Angewandte Chemie International Edition, online article

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. Hereby, an azide building block reacts first with an ethynylphosphonite via the Staudinger‐phosphonite reaction (SPhR) to an ethynylphosphonamidate. The resulting electron‐deficient triple bond subsequently undergoes a cysteine‐selective reaction with proteins or antibodies. We demonstrate that ethynylphosphonamidates hold excellent cysteine‐selective reactivity combined with a superior stability of the thiol adducts. This turns our technique into a versatile and powerful tool for the facile construction of stable, functional protein conjugates.

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