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Structure-Based Design of Potent Tumor-Associated Antigens: Modulation of Peptide Presentation by Single-Atom O/S or O/Se Substitutions at the Glycosidic Linkage

  • Datos identificativos

    Identificador: imarina:5873698
    Handle: https://hdl.handle.net/20.500.11797/imarina5873698
    Autores:
    Companon, IsmaelGuerreiro, AnaMangini, VincenzoCastro-Lopez, JorgeEscudero-Casao, MargaritaAvenoza, AlbertoBusto, Jesus HCastillon, SergioJimenez-Barbero, JesusAsensio, Juan LJimenez-Oses, GonzaloBoutureira, OmarPeregrina, Jesus MHurtado-Guerrero, RamonFiammengo, RobertoBernardes, Goncalo J LCorzana, Francisco
    Resumen:
    GalNAc-glycopeptides derived from mucin MUC1 are an important class of tumor-associated antigens. α- O-glycosylation forces the peptide to adopt an extended conformation in solution, which is far from the structure observed in complexes with a model anti-MUC1 antibody. Herein, we propose a new strategy for designing potent antigen mimics based on modulating peptide/carbohydrate interactions by means of O → S/Se replacement at the glycosidic linkage. These minimal chemical modifications bring about two key structural changes to the glycopeptide. They increase the carbohydrate-peptide distance and change the orientation and dynamics of the glycosidic linkage. As a result, the peptide acquires a preorganized and optimal structure suited for antibody binding. Accordingly, these new glycopeptides display improved binding toward a representative anti-MUC1 antibody relative to the native antigens. To prove the potential of these glycopeptides as tumor-associated MUC1 antigen mimics, the derivative bearing the S-glycosidic linkage was conjugated to gold nanoparticles and tested as an immunogenic formulation in mice without any adjuvant, which resulted in a significant humoral immune response. Importantly, the mice antisera recognize cancer cells in biopsies of breast cancer patients with high selectivity. This finding demonstrates that the antibodies elicited against the mimetic antigen indeed recognize the naturally occurring antigen in its physiological context. Clinically, the exploitation of tumor-associated antigen mimics may contribute to the development of cancer vaccines and to the improvement of cancer diagnosis based on anti-MUC1 antibodies. The methodology presented here is of general interest for applications because it may be extended to modulate the affinity of bi

  • Otros:

    Autor según el artículo: Companon, Ismael; Guerreiro, Ana; Mangini, Vincenzo; Castro-Lopez, Jorge; Escudero-Casao, Margarita; Avenoza, Alberto; Busto, Jesus H; Castillon, Sergio; Jimenez-Barbero, Jesus; Asensio, Juan L; Jimenez-Oses, Gonzalo; Boutureira, Omar; Peregrina, Jesus M; Hurtado-Guerrero, Ramon; Fiammengo, Roberto; Bernardes, Goncalo J L; Corzana, Francisco
    Departamento: Química Analítica i Química Orgànica
    Autor/es de la URV: Boutureira Martín, Omar / Castillón Miranda, Sergio
    Palabras clave: Vaccines Tn-antigen Sulfur Selenium Oxygen O-glycosylation Muc1 Molecular structure Molecular recognition Mice, inbred balb c Mice Mammary neoplasms, experimental Humans Glycosylation Glycosides Glycopeptides Female Drug design Conformations Carbohydrates Carbohydrate Cancer Breast neoplasms Antigens, neoplasm Antibodies, monoclonal Antibodies Animals
    Resumen: GalNAc-glycopeptides derived from mucin MUC1 are an important class of tumor-associated antigens. α- O-glycosylation forces the peptide to adopt an extended conformation in solution, which is far from the structure observed in complexes with a model anti-MUC1 antibody. Herein, we propose a new strategy for designing potent antigen mimics based on modulating peptide/carbohydrate interactions by means of O → S/Se replacement at the glycosidic linkage. These minimal chemical modifications bring about two key structural changes to the glycopeptide. They increase the carbohydrate-peptide distance and change the orientation and dynamics of the glycosidic linkage. As a result, the peptide acquires a preorganized and optimal structure suited for antibody binding. Accordingly, these new glycopeptides display improved binding toward a representative anti-MUC1 antibody relative to the native antigens. To prove the potential of these glycopeptides as tumor-associated MUC1 antigen mimics, the derivative bearing the S-glycosidic linkage was conjugated to gold nanoparticles and tested as an immunogenic formulation in mice without any adjuvant, which resulted in a significant humoral immune response. Importantly, the mice antisera recognize cancer cells in biopsies of breast cancer patients with high selectivity. This finding demonstrates that the antibodies elicited against the mimetic antigen indeed recognize the naturally occurring antigen in its physiological context. Clinically, the exploitation of tumor-associated antigen mimics may contribute to the development of cancer vaccines and to the improvement of cancer diagnosis based on anti-MUC1 antibodies. The methodology presented here is of general interest for applications because it may be extended to modulate the affinity of biologically relevant glycopeptides toward their receptors.
    Áreas temáticas: Química Materiais Interdisciplinar General chemistry Farmacia Engenharias iv Engenharias iii Engenharias ii Colloid and surface chemistry Ciências biológicas ii Ciências biológicas i Ciências agrárias i Ciência de alimentos Chemistry, multidisciplinary Chemistry (miscellaneous) Chemistry (all) Chemistry Catalysis Biochemistry Astronomia / física
    Acceso a la licencia de uso: https://creativecommons.org/licenses/by/3.0/es/
    ISSN: 00027863
    Direcció de correo del autor: omar.boutureira@urv.cat sergio.castillon@urv.cat
    Identificador del autor: 0000-0002-0768-8309 0000-0002-0690-7549
    Fecha de alta del registro: 2024-11-30
    Versión del articulo depositado: info:eu-repo/semantics/acceptedVersion
    URL Documento de licencia: https://repositori.urv.cat/ca/proteccio-de-dades/
    Referencia al articulo segun fuente origial: Journal Of The American Chemical Society. 141 (9): 4063-4072
    Referencia de l'ítem segons les normes APA: Companon, Ismael; Guerreiro, Ana; Mangini, Vincenzo; Castro-Lopez, Jorge; Escudero-Casao, Margarita; Avenoza, Alberto; Busto, Jesus H; Castillon, Serg (2019). Structure-Based Design of Potent Tumor-Associated Antigens: Modulation of Peptide Presentation by Single-Atom O/S or O/Se Substitutions at the Glycosidic Linkage. Journal Of The American Chemical Society, 141(9), 4063-4072. DOI: 10.1021/jacs.8b13503
    Entidad: Universitat Rovira i Virgili
    Año de publicación de la revista: 2019
    Tipo de publicación: Journal Publications

  • Palabras clave:

    Biochemistry,Catalysis,Chemistry,Chemistry (Miscellaneous),Chemistry, Multidisciplinary,Colloid and Surface Chemistry
    Vaccines
    Tn-antigen
    Sulfur
    Selenium
    Oxygen
    O-glycosylation
    Muc1
    Molecular structure
    Molecular recognition
    Mice, inbred balb c
    Mice
    Mammary neoplasms, experimental
    Humans
    Glycosylation
    Glycosides
    Glycopeptides
    Female
    Drug design
    Conformations
    Carbohydrates
    Carbohydrate
    Cancer
    Breast neoplasms
    Antigens, neoplasm
    Antibodies, monoclonal
    Antibodies
    Animals
    Química
    Materiais
    Interdisciplinar
    General chemistry
    Farmacia
    Engenharias iv
    Engenharias iii
    Engenharias ii
    Colloid and surface chemistry
    Ciências biológicas ii
    Ciências biológicas i
    Ciências agrárias i
    Ciência de alimentos
    Chemistry, multidisciplinary
    Chemistry (miscellaneous)
    Chemistry (all)
    Chemistry
    Catalysis
    Biochemistry
    Astronomia / física

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