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

The 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 preferenc...

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Autores: Bermejo, Iris A, Navo, Claudio D., Castro López, Jorge, Guerreiro, Ana, Jiménez Moreno, Ester, Sánchez Fernández, Elena Matilde, Ortiz Mellet, Carmen, Corzana, Francisco
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/130645
Acceso en línea:https://hdl.handle.net/11441/130645
https://doi.org/10.1039/c9sc06334j
Access Level:acceso abierto
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spelling Synthesis, conformational analysis and: In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragmentBermejo, Iris ANavo, Claudio D.Castro López, JorgeGuerreiro, AnaJiménez Moreno, EsterSánchez Fernández, Elena MatildeOrtiz Mellet, CarmenCorzana, FranciscoThe 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.Ministerio de Ciencia, Innovación y Universidades RTI2018-099592-B-C21 and RTI2018-097609-B-C21Ministerio de Economía y Competitividad SAF2016-76083-RFundação para a Ciência e a Tecnologia SFRH/BD/115932/2016, IF/00624/2015MEC CTQ2013-44367-C2-2-P and BFU2016-75633-PGobierno de Aragón E34_R17 and LMP58_18BioStruct-X FP7 442The Royal Society URF\R\180019Royal Society of ChemistryQuímica OrgánicaMinisterio de Ciencia, Innovación y Universidades (MICINN). EspañaMinisterio de Economía y Competitividad (MINECO). EspañaFundação para a Ciência e a Tecnologia. PortugalRoyal Society (UK)Ministerio de Educación y Ciencia (MEC). EspañaGobierno de AragónEuropean Commission (EC)2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/130645https://doi.org/10.1039/c9sc06334jreponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésChemical Science, 11 (15), 3996-4006.RTI2018-099592-B-C21RTI2018-097609-B-C21SAF2016-76083-RSFRH/BD/115932/2016IF/00624/2015CTQ2013-44367-C2-2-PBFU2016-75633-PE34_R17LMP58_18BioStruct-X FP7 442URF\R\180019http://dx.doi.org/10.1039/c9sc06334jinfo:eu-repo/semantics/openAccessoai:idus.us.es:11441/1306452026-06-17T12:51:07Z
dc.title.none.fl_str_mv Synthesis, conformational analysis and: In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
title Synthesis, conformational analysis and: In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
spellingShingle Synthesis, conformational analysis and: In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
Bermejo, Iris A
title_short Synthesis, conformational analysis and: In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
title_full Synthesis, conformational analysis and: In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
title_fullStr Synthesis, conformational analysis and: In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
title_full_unstemmed Synthesis, conformational analysis and: In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
title_sort Synthesis, conformational analysis and: In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
dc.creator.none.fl_str_mv Bermejo, Iris A
Navo, Claudio D.
Castro López, Jorge
Guerreiro, Ana
Jiménez Moreno, Ester
Sánchez Fernández, Elena Matilde
Ortiz Mellet, Carmen
Corzana, Francisco
author Bermejo, Iris A
author_facet Bermejo, Iris A
Navo, Claudio D.
Castro López, Jorge
Guerreiro, Ana
Jiménez Moreno, Ester
Sánchez Fernández, Elena Matilde
Ortiz Mellet, Carmen
Corzana, Francisco
author_role author
author2 Navo, Claudio D.
Castro López, Jorge
Guerreiro, Ana
Jiménez Moreno, Ester
Sánchez Fernández, Elena Matilde
Ortiz Mellet, Carmen
Corzana, Francisco
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Química Orgánica
Ministerio de Ciencia, Innovación y Universidades (MICINN). España
Ministerio de Economía y Competitividad (MINECO). España
Fundação para a Ciência e a Tecnologia. Portugal
Royal Society (UK)
Ministerio de Educación y Ciencia (MEC). España
Gobierno de Aragón
European Commission (EC)
description The 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.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/130645
https://doi.org/10.1039/c9sc06334j
url https://hdl.handle.net/11441/130645
https://doi.org/10.1039/c9sc06334j
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Chemical Science, 11 (15), 3996-4006.
RTI2018-099592-B-C21
RTI2018-097609-B-C21
SAF2016-76083-R
SFRH/BD/115932/2016
IF/00624/2015
CTQ2013-44367-C2-2-P
BFU2016-75633-P
E34_R17
LMP58_18
BioStruct-X FP7 442
URF\R\180019
http://dx.doi.org/10.1039/c9sc06334j
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Royal Society of Chemistry
publisher.none.fl_str_mv Royal Society of Chemistry
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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