Quaternization of Vinyl/Alkynyl Pyridine Enables Ultrafast Cysteine-Selective Protein Modification and Charge Modulation

Autor(es):Mostrar menos -

Matos, Maria J. ^[1] ; Navo, Claudio D. ^{[2, 3]} ; Hakala, Tuuli ^[1] ; Ferhati, Xhenti ^[2] ; Guerreiro, Ana ^[4] ; Hartmann, David ^[1] ; Bernardim, Barbara ^[1] ; Saar, Kadi L. ^[1] ; Companon, Ismael ^[2] ; Corzana, Francisco ^[2] ; Knowles, Tuomas P. J. ^[1] ; Jimenez-Oses, Gonzalo ^{[2, 3]} ; Bernardes, Goncalo J. L. ^{[1, 4]}

Afiliação do(s) autor(es)

^[1] Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW - England

^[2] Univ La Rioja, Dept Quim, Ctr Invest Sintesis Qum, Logrono - Spain

^[3] CIC bioGUNE, Bizkaia Technol Pk, Bldg 801A, Derio 48170 - Spain

^[4] Univ Lisbon, Inst Med Mol, Fac Med, Ave Prof Egas Moniz, P-1649028 Lisbon - Portugal

• Tipo de documento: Artigo Científico
• Fonte: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION; v. 58, n. 20, p. 6640-6644, MAY 13 2019.
• Citações Web of Science: 1

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. (AU)

• Processo FAPESP: 15/07509-1 - Modificação específica de proteínas via reação de Horner-Wadsworth-Emmons seguida de rearranjo de Wolff
• Beneficiário: Barbara Bernardim de Souza
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 17/13168-8 - Construção de conjugados anticorpo-droga quimicamente definidos utilizando reagentes carbonilacrílicos
• Beneficiário: Barbara Bernardim de Souza
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado