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

2019Artigo científico Acesso aberto
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dc.contributor.authorMatos, Maria J.
dc.contributor.authorNavo, Claudio D.
dc.contributor.authorHakala, Tuuli
dc.contributor.authorFerhati, Xhenti
dc.contributor.authorGuerreiro, Ana
dc.contributor.authorHartmann, David
dc.contributor.authorBernardim, Barbara
dc.contributor.authorSaar, Kadi L.
dc.contributor.authorCompañón, Ismael
dc.contributor.authorCorzana, Francisco
dc.contributor.authorKnowles, Tuomas P. J.
dc.contributor.authorJiménez‐Osés, Gonzalo
dc.contributor.authorBernardes, Gonçalo J. L.
dc.date.accessioned2022-05-10T14:18:55Z
dc.date.available2022-05-10T14:18:55Z
dc.date.issued2019
dc.description© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.pt_PT
dc.description.abstractQuaternized 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.pt_PT
dc.description.sponsorshipFunded under the EU Horizon 2020 Programme, Marie Skłodowska-Curie ITN GA No. 675007, the Royal Society (UF110046 and URF\R\180019 to G.J.L.B.), FCT Portugal (iFCT IF/00624/2015 to G.J.L.B. and PhD studentship SFRH/BD/115932/2016 to A.G.), Xunta de Galicia (Galician Plan of research, innovation and growth 2011–2015, ED481B 2014/086-0 and ED481B 2018/007 to M.J.M.), D.G.I. MINECO/FEDER (grants CTQ2015-70524-R and RYC-2013–14706 to G.J.-O. and C.D.N and CTQ2015-67727-R to F.C.), Universidad de la Rioja (FPI PhD studentship to I.C.), FAPESP (BEPE 2015/07509-1 and 2017/13168-8 to B.B.), and by an ERC StG (GA No. 676832).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAngew Chem Int Ed Engl. 2019 May 13;58(20):6640-6644pt_PT
dc.identifier.doi10.1002/anie.201901405pt_PT
dc.identifier.eissn1521-3773
dc.identifier.issn1433-7851
dc.identifier.urihttp://hdl.handle.net/10451/52854
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.relationModulation and targeting of calcium channels with ligand-drug conjugates for cancer therapy
dc.relationSynthetically-defined glycoconjugate vaccine candidates against Influenza
dc.relation.publisherversionhttps://onlinelibrary.wiley.com/journal/15213773pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAntibody-drug conjugatespt_PT
dc.subjectBioconjugationpt_PT
dc.subjectCysteinept_PT
dc.subjectMicrofluidicspt_PT
dc.subjectProtein modificationpt_PT
dc.titleQuaternization of Vinyl/Alkynyl Pyridine enables ultrafast cysteine‐selective protein modification and charge modulationpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberIF/00624/2015/CP1287/CT0002
oaire.awardNumberSFRH/BD/115932/2016
oaire.awardTitleModulation and targeting of calcium channels with ligand-drug conjugates for cancer therapy
oaire.awardTitleSynthetically-defined glycoconjugate vaccine candidates against Influenza
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F00624%2F2015%2FCP1287%2FCT0002/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F115932%2F2016/PT
oaire.citation.endPage6644pt_PT
oaire.citation.issue20pt_PT
oaire.citation.startPage6640pt_PT
oaire.citation.titleAngewandte Chemie International Editionpt_PT
oaire.citation.volume58pt_PT
oaire.fundingStreamInvestigador FCT
oaire.fundingStreamOE
person.familyNamedos Santos Guerreiro
person.familyNameBernardes
person.givenNameAna Maria
person.givenNameGonçalo
person.identifier.ciencia-id481C-A494-B69D
person.identifier.orcid0000-0002-2173-6514
person.identifier.orcid0000-0001-6594-8917
person.identifier.scopus-author-id14046757500
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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