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Enhancing Cancer Vaccine Efficacy

2025-05-15Artigo científico Acesso aberto
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dc.contributor.authorGibadullin, Ruslan
dc.contributor.authorSuárez, Óscar
dc.contributor.authorLazaris, Foivos S.
dc.contributor.authorGutiez, Naiara
dc.contributor.authorAtondo, Estibaliz
dc.contributor.authorAraujo-Aris, Sarai
dc.contributor.authorEguskiza, Ander
dc.contributor.authorNiu, Jiani
dc.contributor.authorKuhn, Ariel J.
dc.contributor.authorGrosso, Ana S.
dc.contributor.authorRodriguez, Héctor
dc.contributor.authorGarcía-Martín, Fayna
dc.contributor.authorMarcelo, Filipa
dc.contributor.authorSantos, Tanausú
dc.contributor.authorAvenoza, Alberto
dc.contributor.authorBusto, Jesús H.
dc.contributor.authorPeregrina, Jesús M.
dc.contributor.authorGellman, Samuel H.
dc.contributor.authorAnguita, Juan
dc.contributor.authorFiammengo, Roberto
dc.contributor.authorCorzana, Francisco
dc.contributor.institutionUCIBIO - Applied Molecular Biosciences Unit
dc.contributor.institutionDQ - Departamento de Química
dc.contributor.pblACS - American Chemical Society
dc.date.accessioned2025-07-26T21:19:00Z
dc.date.available2025-07-26T21:19:00Z
dc.date.issued2025-05-15
dc.descriptionFunding Information: This project has received partial funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 956544. This work was also supported in part by the National Institutes of Health grant (R01 GM056414 and its successor R35 GM151985) awarded to S.H.G. We thank the Agencia Estatal de Investigación (AEI, PID2021-127622OB-I00 to F.C., J.H.B. and O.S., PDC2022-133725-C21 to F.C, J.H.B., PID2020-120099RA-I00 to F.G.M., PID2021-124328OB-100 to J.A., and PRE-2019-091720 to S.A.), Universidad de La Rioja (REGI22/47 and REGI22/16) and Asociación Española contra el Cáncer (AECC) sección La Rioja (F.C. and J.M.P.). F.M. and A.S.G. acknowledge Fundação para a Ciência e Tecnologia Portugal (FCT-Portugal) for the MGL4Life project 10.54499/PTDC/QUI-OUT/2586/2020. F.M. thanks FCT-Portugal for CEECINST/00042/2021/CP1773/CT0011. F.M and A.S.G. thank UCIBIO project (UIDP/04378/2020 and UIDB/04378/2020), and Associate Laboratory Institute for Health and Bioeconomy - i4HB project (LA/P/0140/2020) and the National NMR Facility supported by FCT-Portugal (ROTEIRO/0031/2013–PINFRA/22161/2016, cofinanced by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC). T.S. thanks MCIN/AEI/10.13039/501100011033 and the European Union NextGenerationEU/PRTR for his Juan de la Cierva contract, JDC2022-048607-I. N.G. held a predoctoral grant from the Scientific Foundation of the Spanish Association Against Cancer in Bizkaia (PRDVZ222452GUTI). CICbioGUNE is the recipient of a Severo Ochoa Centro de Excelencia Award (CEX2021-001136-S). Supported in part by Fundación Jesús de Gangoiti. We are also grateful for partial support from the Vilas Trust and from the University of Wisconsin-Madison Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation. A.J.K. was supported in part by a postdoctoral fellowship from the National Institutes of Health (5F32AI176876). Publisher Copyright: © 2025 The Authors. Published by American Chemical Society.
dc.description.abstractGlycopeptides derived from the mucin-1 (MUC1) glycoprotein hold significant promise as cancer vaccine candidates, but their clinical utility is limited by proteolytic degradation and the poor bioavailability of L-α-amino acid-based peptides. In this study, we demonstrate that substitution of multiple α-amino acids with homologous β-amino acids (same side chain, but extended backbone) in O-glycosylated MUC1 derivatives significantly enhances their proteolytic stability. We further show that α-to-β substitutions within the most immunogenic epitope of MUC1 impede binding to an anti-MUC1 antibody, while substitutions outside the same epitope preserve antibody recognition. Structural investigations using circular dichroism, NMR spectroscopy, and molecular dynamics simulations reveal that the strongest α/β-peptide binders retain native-like conformations in the epitope region, both in their unbound state and when bound to the anti-MUC1 antibody. Conjugation of these high-affinity α/β-peptide analogs to gold nanoparticles induces robust immune responses in mice comparable to that of the native glycopeptide. Additionally, these α/β-analogs elicit elevated levels of the cytokine IFNγ, one of the key proteins for tumor cell elimination, surpassing levels produced by the native MUC1 glycopeptide. In contrast, a low-affinity α/β-analogue with lower proteolytic stability produces minimal cytokine responses, underscoring the critical role of these biochemical properties in vaccine efficacy. Collectively, our findings highlight that α-to-β modifications in the peptide backbone offer an effective strategy for developing biostable, highly immunogenic glycopeptide-based cancer vaccines, exemplifying the power of structure-based rational design in advancing next-generation vaccines.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent15
dc.format.extent7724808
dc.identifier.doi10.1021/jacsau.5c00224
dc.identifier.issn2691-3704
dc.identifier.otherPURE: 122730195
dc.identifier.otherPURE UUID: b4becf0b-1c53-4c14-9fa2-8ff90db26b80
dc.identifier.otherScopus: 105005351856
dc.identifier.otherWOS: 001489089300001
dc.identifier.otherPubMed: 40443897
dc.identifier.otherPubMedCentral: PMC12117419
dc.identifier.otherORCID: /0000-0001-5049-8511/work/188645060
dc.identifier.urihttp://hdl.handle.net/10362/185586
dc.identifier.urlhttps://www.scopus.com/pages/publications/105005351856
dc.identifier.urlhttps://www.webofscience.com/wos/woscc/full-record/WOS:001489089300001
dc.language.isoeng
dc.peerreviewedyes
dc.relationinfo:eu-repo/grantAgreement/EC/H2020/956544/EU
dc.relationDirecting the immune response through designed nanomaterials
dc.relationApplied Molecular Biosciences Unit
dc.relationApplied Molecular Biosciences Unit
dc.relationinfo:eu-repo/grantAgreement/FCT/Concurso para Atribuição do Estatuto e Financiamento de Laboratórios Associados (LA)/LA%2FP%2F0140%2F2020/PT
dc.subjectCancer vaccine
dc.subjectGlycopeptide
dc.subjectGold nanoparticles
dc.subjectMucin
dc.subjectProteolytic stability
dc.subjectβ-peptides
dc.subjectAnalytical Chemistry
dc.subjectChemistry (miscellaneous)
dc.subjectPhysical and Theoretical Chemistry
dc.subjectOrganic Chemistry
dc.subjectSDG 3 - Good Health and Well-being
dc.titleEnhancing Cancer Vaccine Efficacyen
dc.title.subtitleBackbone Modification with β-Amino Acids Alters the Stability and Immunogenicity of MUC1-Derived Glycopeptide Formulationsen
dc.typejournal article
degois.publication.firstPage2270
degois.publication.issue5
degois.publication.lastPage2284
degois.publication.titleJACS Au
degois.publication.volume5
dspace.entity.typePublication
oaire.awardNumber956544
oaire.awardNumberPTDC/QUI-OUT/2586/2020
oaire.awardNumberUIDP/04378/2020
oaire.awardNumberUIDB/04378/2020
oaire.awardNumberLA/P/0140/2020
oaire.awardTitleDirecting the immune response through designed nanomaterials
oaire.awardTitleApplied Molecular Biosciences Unit
oaire.awardTitleApplied Molecular Biosciences Unit
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/956544/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Concurso para Financiamento de Projetos de Investigação Científica e Desenvolvimento Tecnológico em Todos os Domínios Científicos - 2020/PTDC%2FQUI-OUT%2F2586%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04378%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04378%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Concurso para Atribuição do Estatuto e Financiamento de Laboratórios Associados (LA)/LA%2FP%2F0140%2F2020/PT
oaire.fundingStreamH2020
oaire.fundingStreamConcurso para Financiamento de Projetos de Investigação Científica e Desenvolvimento Tecnológico em Todos os Domínios Científicos - 2020
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamConcurso para Atribuição do Estatuto e Financiamento de Laboratórios Associados (LA)
project.funder.identifierhttp://doi.org/10.13039/501100008530
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project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameEuropean Commission
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
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