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Diethynyl Phosphinates for Cysteine‐Selective Protein Labeling and Disulfide Rebridging
Author(s) -
Stieger Christian E.,
Franz Luise,
Körlin Frieder,
Hackenberger Christian P. R.
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202100683
Subject(s) - moiety , conjugate , electrophile , chemistry , thiol , cysteine , combinatorial chemistry , reagent , bioconjugation , disulfide bond , stereochemistry , biochemistry , organic chemistry , catalysis , mathematical analysis , mathematics , enzyme
Diethynyl phosphinates were developed as bisfunctional electrophiles for the site‐selective modification of peptides, proteins and antibodies. One of their electron‐deficient triple bonds reacts selectively with a thiol and positions an electrophilic moiety for a subsequent intra‐ or intermolecular reaction with another thiol. The obtained conjugates were found to be stable in human plasma and in the presence of small thiols. We further demonstrate that this method is suitable for the generation of functional protein conjugates for intracellular delivery. Finally, this reagent class was used to generate functional homogeneously rebridged antibodies that remain specific for their target. Their modular synthesis, thiol selectivity and conjugate stability make diethynyl phosphinates ideal candidates for protein conjugation for biological and pharmaceutical applications.