期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 58, 期 20, 页码 6640-6644出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201901405
关键词
antibody-drug conjugates; bioconjugation; cysteine; microfluidics; protein modification
资金
- EU Horizon 2020 Programme
- Marie Skodowska-Curie ITN GA [675007]
- Royal Society [UF110046, URF\R\180019]
- FCT Portugal [iFCT IF/00624/2015, SFRH/BD/115932/2016]
- Xunta de Galicia (Galician Plan of research, innovation and growth) [ED481B 2014/086-0, ED481B 2018/007]
- D.G.I. MINECO/FEDER [CTQ2015-70524-R, RYC-2013-14706, CTQ2015-67727-R]
- Universidad de la Rioja (FPI PhD studentship)
- FAPESP [BEPE 2015/07509-1, 2017/13168-8]
- ERC StG [676832]
- Marie Curie Actions (MSCA) [675007] Funding Source: Marie Curie Actions (MSCA)
- Royal Society [UF110046] Funding Source: Royal Society
- Fundação para a Ciência e a Tecnologia [SFRH/BD/115932/2016] Funding Source: FCT
- European Research Council (ERC) [676832] Funding Source: European Research Council (ERC)
Quaternized vinyl- and alkynyl-pyridine reagents were shown to react in an ultrafast and selective manner with several cysteine-tagged proteins at near-stoichiometric quantities. We have demonstrated that this method can effectively create a homogenous antibody-drug conjugate that features a precise drug-to-antibody ratio of 2, which was stable in human plasma and retained its specificity towards Her2+ cells. Finally, the developed warhead introduces a +1 charge to the overall net charge of the protein, which enabled us to show that the electrophoretic mobility of the protein may be tuned through the simple attachment of a quaternized vinyl pyridinium reagent at the cysteine residues. We anticipate the generalized use of quaternized vinyl- and alkynyl-pyridine reagents not only for bioconjugation, but also as warheads for covalent inhibition and as tools to profile cysteine reactivity.
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