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

Ismael Compan, Ana Guerreiro, Vincenzo Mangini, Jorge Castro-Lopez, Margarita Escudero-Casao, Alberto Avenoza, Jesus H. Busto, Sergio Castillón, Jesús Jiménez-Barbero, Juan L. Asensio, Gonzalo Jimenerz- Oses, Omar Boutureira, Jesus M. Peregrina, Ramón Hurtado-Guerrero, Roberto Fiammengo, Gonçalo J. L. Bernardes, Francisco Corzana.
J. Am. Chem. Soc. 2019, 141, 4063−4072

Herein, we propose a new strategy for designing potent antigen mimics by means of O → S/Se replacement at the glycosidic linkage. These minimal chemical modifications 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. 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.

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