Synthesis, conformational analysis and in vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2020 |
| Outros Autores: | , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10451/49896 |
Resumo: | This journal is © The Royal Society of Chemistry 2020. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. |
| id |
RCAP_07abf3cebe813e2324bfbf64736489b9 |
|---|---|
| oai_identifier_str |
oai:repositorio.ul.pt:10451/49896 |
| network_acronym_str |
RCAP |
| network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| repository_id_str |
7160 |
| spelling |
Synthesis, conformational analysis and in vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragmentThis journal is © The Royal Society of Chemistry 2020. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.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.We 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.Royal Society of ChemistryRepositório da Universidade de LisboaBermejo, Iris A.Navo, Claudio D.Castro-López, JorgeGuerreiro, AnaJiménez-Moreno, EsterSánchez Fernández, Elena M.García-Martín, FaynaHinou, HiroshiNishimura, Shin-IchiroGarcía Fernández, José M.Mellet, Carmen OrtizAvenoza, AlbertoBusto, Jesús H.Bernardes, Gonçalo J. L.Hurtado-Guerrero, RamónPeregrina, Jesús M.Corzana, Francisco2021-10-15T12:57:54Z20202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/49896engChem Sci. 2020 Mar 27;11(15):3996-40062041-652010.1039/C9SC06334J2041-6539info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:53:51Zoai:repositorio.ul.pt:10451/49896Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:01:25.389169Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
| 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 |
| author |
Bermejo, Iris A. |
| author_facet |
Bermejo, Iris A. Navo, Claudio D. Castro-López, Jorge Guerreiro, Ana Jiménez-Moreno, Ester Sánchez Fernández, Elena M. García-Martín, Fayna Hinou, Hiroshi Nishimura, Shin-Ichiro García Fernández, José M. Mellet, Carmen Ortiz Avenoza, Alberto Busto, Jesús H. Bernardes, Gonçalo J. L. Hurtado-Guerrero, Ramón Peregrina, Jesús M. Corzana, Francisco |
| author_role |
author |
| author2 |
Navo, Claudio D. Castro-López, Jorge Guerreiro, Ana Jiménez-Moreno, Ester Sánchez Fernández, Elena M. García-Martín, Fayna Hinou, Hiroshi Nishimura, Shin-Ichiro García Fernández, José M. Mellet, Carmen Ortiz Avenoza, Alberto Busto, Jesús H. Bernardes, Gonçalo J. L. Hurtado-Guerrero, Ramón Peregrina, Jesús M. Corzana, Francisco |
| author2_role |
author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
Bermejo, Iris A. Navo, Claudio D. Castro-López, Jorge Guerreiro, Ana Jiménez-Moreno, Ester Sánchez Fernández, Elena M. García-Martín, Fayna Hinou, Hiroshi Nishimura, Shin-Ichiro García Fernández, José M. Mellet, Carmen Ortiz Avenoza, Alberto Busto, Jesús H. Bernardes, Gonçalo J. L. Hurtado-Guerrero, Ramón Peregrina, Jesús M. Corzana, Francisco |
| description |
This journal is © The Royal Society of Chemistry 2020. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 2020-01-01T00:00:00Z 2021-10-15T12:57:54Z |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
| dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/49896 |
| url |
http://hdl.handle.net/10451/49896 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
Chem Sci. 2020 Mar 27;11(15):3996-4006 2041-6520 10.1039/C9SC06334J 2041-6539 |
| dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
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:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
| instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
| instacron_str |
RCAAP |
| institution |
RCAAP |
| reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
| repository.mail.fl_str_mv |
|
| _version_ |
1799134562680307712 |