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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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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]
Total Authors: 13
Affiliation:
[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
Total Affiliations: 4
Document type: Journal article
Source: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION; v. 58, n. 20, p. 6640-6644, MAY 13 2019.
Web of Science Citations: 1
Abstract

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)

FAPESP's process: 15/07509-1 - Site-specific modification of proteins via aqueous Horner-Wadsworth-Emmons reaction followed by Wolff rearrangement
Grantee:Barbara Bernardim de Souza
Support type: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 17/13168-8 - Construction of chemically defined antibody-drug conjugates using carbonylacrylic reagents
Grantee:Barbara Bernardim de Souza
Support type: Scholarships abroad - Research Internship - Post-doctor