期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 28, 页码 15359-15364出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202100683
关键词
antibody rebridging; bioconjugation; cysteine-selective modification; phosphorous-based electrophiles; protein double-modification
资金
- Deutsche Forschungsgemeinschaft (DFG) [SPP1623 HA 4468/10-1, RTG GRK2473]
- Leibniz Society (SAW-2018-FMP-4-P5label) [T18/2017]
- Einstein Foundation Berlin (Leibniz-Humboldt Professorship)
- Studienstiftung des Deutschen Volkes
- Projekt DEAL
Diethynyl phosphinates are developed as bisfunctional electrophiles for site-selective modification of peptides, proteins, and antibodies. The obtained conjugates are stable in human plasma and in the presence of small thiols. This method is suitable for generating functional protein conjugates, including homogeneously rebridged antibodies that remain specific for their target.
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.
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