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Quaternization of Vinyl/Alkynyl Pyridine enables ultrafast cysteine‐selective protein modification and charge modulation

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Resumo: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.
Autores principais:Matos, Maria J.
Outros Autores:Navo, Claudio D.; Hakala, Tuuli; Ferhati, Xhenti; Guerreiro, Ana; Hartmann, David; Bernardim, Barbara; Saar, Kadi L.; Compañón, Ismael; Corzana, Francisco; Knowles, Tuomas P. J.; Jiménez‐Osés, Gonzalo; Bernardes, Gonçalo J. L.
Assunto:Antibody-drug conjugates Bioconjugation Cysteine Microfluidics Protein modification
Ano:2019
País:Portugal
Tipo de documento:artigo
Tipo de acesso:acesso aberto
Instituição associada:Universidade de Lisboa
Idioma:inglês
Origem:Repositório da Universidade de Lisboa

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