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Synthesis, conformational analysis and in vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment

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dc.contributor.authorBermejo, Iris A.
dc.contributor.authorNavo, Claudio D.
dc.contributor.authorCastro-López, Jorge
dc.contributor.authorGuerreiro, Ana
dc.contributor.authorJiménez-Moreno, Ester
dc.contributor.authorSánchez Fernández, Elena M.
dc.contributor.authorGarcía-Martín, Fayna
dc.contributor.authorHinou, Hiroshi
dc.contributor.authorNishimura, Shin-Ichiro
dc.contributor.authorGarcía Fernández, José M.
dc.contributor.authorMellet, Carmen Ortiz
dc.contributor.authorAvenoza, Alberto
dc.contributor.authorBusto, Jesús H.
dc.contributor.authorBernardes, Gonçalo J. L.
dc.contributor.authorHurtado-Guerrero, Ramón
dc.contributor.authorPeregrina, Jesús M.
dc.contributor.authorCorzana, Francisco
dc.date.accessioned2021-10-15T12:57:54Z
dc.date.available2021-10-15T12:57:54Z
dc.date.issued2020
dc.descriptionThis journal is © The Royal Society of Chemistry 2020. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.pt_PT
dc.description.abstractThe Tn antigen (GalNAc-α-1-O-Thr/Ser) is a well-known tumor-associated carbohydrate determinant. The use of glycopeptides that incorporate this structure has become a significant and promising niche of research owing to their potential use as anticancer vaccines. Herein, the conformational preferences of a glycopeptide with an unnatural Tn antigen, characterized by a threonine decorated with an sp2-iminosugar-type α-GalNAc mimic, have been studied both in solution, by combining NMR spectroscopy and molecular dynamics simulations, and in the solid state bound to an anti-mucin-1 (MUC1) antibody, by X-ray crystallography. The Tn surrogate can mimic the main conformer sampled by the natural antigen in solution and exhibits high affinity towards anti-MUC1 antibodies. Encouraged by these data, a cancer vaccine candidate based on this unnatural glycopeptide and conjugated to the carrier protein Keyhole Limpet Hemocyanin (KLH) has been prepared and tested in mice. Significantly, the experiments in vivo have proved that this vaccine elicits higher levels of specific anti-MUC1 IgG antibodies than the analog that bears the natural Tn antigen and that the elicited antibodies recognize human breast cancer cells with high selectivity. Altogether, we compile evidence to confirm that the presentation of the antigen, both in solution and in the bound state, plays a critical role in the efficacy of the designed cancer vaccines. Moreover, the outcomes derived from this vaccine prove that there is room for exploring further adjustments at the carbohydrate level that could contribute to designing more efficient cancer vaccines.pt_PT
dc.description.sponsorshipWe acknowledge the Ministerio de Ciencia, Innovación y Universidades and the Agencia Estatal de Investigación (projects RTI2018-099592-B-C21 and RTI2018-097609-B-C21), the Ministerio de Economía y Competitividad (SAF2016-76083-R), European Regional Development Funds (FEDER-UE), the Royal Society (URF\R\180019 to G. J. L. B.) and FCT Portugal (PhD studentship, SFRH/BD/115932/2016 to A. G. and FCT Investigator IF/00624/2015 to G. J. L. B.). M. C. O further thanks CITIUS for technical support. I. A. B. thanks the Asociación Española Contra el Cancer en La Rioja for a grant. E. J.-M. thanks Universidad de La Rioja for a postdoctoral fellowship. R. H.-G. acknowledges Diamond Light Source (Oxford, UK) synchrotron beamline I04 (experiment numbers mx10121-19). He also acknowledges ARAID, MEC (CTQ2013-44367-C2-2-P and BFU2016-75633-P) and Gobierno de Aragón (E34_R17 and LMP58_18) with FEDER (2014–2020) funds for ‘Building Europe from Aragón’ for financial support. The research leading to these results has also received funding from FP7 442 (2007–2013) under BioStruct-X (grant agreement no. 283570 and BIOSTRUCTX_5186). F. G.-M. of Hokkaido University acknowledges grant from the Naito Foundation.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationChem Sci. 2020 Mar 27;11(15):3996-4006pt_PT
dc.identifier.doi10.1039/C9SC06334Jpt_PT
dc.identifier.eissn2041-6539
dc.identifier.issn2041-6520
dc.identifier.urihttp://hdl.handle.net/10451/49896
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherRoyal Society of Chemistrypt_PT
dc.relationIF/00624/2015pt_PT
dc.relationSynthetically-defined glycoconjugate vaccine candidates against Influenza
dc.relation.publisherversionhttps://pubs.rsc.org/en/journals/journalissues/sc#!recentarticles&advpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/pt_PT
dc.titleSynthesis, conformational analysis and in vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragmentpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleSynthetically-defined glycoconjugate vaccine candidates against Influenza
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F115932%2F2016/PT
oaire.citation.endPage4006pt_PT
oaire.citation.issue15pt_PT
oaire.citation.startPage3996pt_PT
oaire.citation.titleChemical Sciencept_PT
oaire.citation.volume11pt_PT
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.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication1c4166db-cf53-48ab-9e3f-476f142cb304
relation.isAuthorOfPublicationd1a48067-77b1-4413-b1c7-602fb18c62c0
relation.isAuthorOfPublication.latestForDiscoveryd1a48067-77b1-4413-b1c7-602fb18c62c0
relation.isProjectOfPublication72b09169-6451-479e-b385-b00cd1aeec59
relation.isProjectOfPublication.latestForDiscovery72b09169-6451-479e-b385-b00cd1aeec59

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