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Enhancing Cancer Vaccine Efficacy
Publication . Gibadullin, Ruslan; Suárez, Óscar; Lazaris, Foivos S.; Gutiez, Naiara; Atondo, Estibaliz; Araujo-Aris, Sarai; Eguskiza, Ander; Niu, Jiani; Kuhn, Ariel J.; Grosso, Ana S.; Rodriguez, Héctor; García-Martín, Fayna; Marcelo, Filipa; Santos, Tanausú; Avenoza, Alberto; Busto, Jesús H.; Peregrina, Jesús M.; Gellman, Samuel H.; Anguita, Juan; Fiammengo, Roberto; Corzana, Francisco; UCIBIO - Applied Molecular Biosciences Unit; DQ - Departamento de Química; ACS - American Chemical Society
Glycopeptides 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.
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Fundação para a Ciência e a Tecnologia
Programa de financiamento
Concurso para Financiamento de Projetos de Investigação Científica e Desenvolvimento Tecnológico em Todos os Domínios Científicos - 2020
Número da atribuição
PTDC/QUI-OUT/2586/2020