Author, as appears in the article.: 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
Department: Química Analítica i Química Orgànica
URV's Author/s: Boutureira Martín, Omar / Castillón Miranda, Sergio
Keywords: 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
Abstract: 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.
Thematic Areas: 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
licence for use: https://creativecommons.org/licenses/by/3.0/es/
ISSN: 00027863
Author's mail: omar.boutureira@urv.cat sergio.castillon@urv.cat
Author identifier: 0000-0002-0768-8309 0000-0002-0690-7549
Record's date: 2024-11-30
Papper version: info:eu-repo/semantics/acceptedVersion
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Papper original source: Journal Of The American Chemical Society. 141 (9): 4063-4072
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
Entity: Universitat Rovira i Virgili
Journal publication year: 2019
Publication Type: Journal Publications
Repositori URV