Reconocimiento Molecular de Análogos de Antígenos Tn como Base para el Diseño de Vacunas Terapéuticas contra el Cáncer

Abstract

Mucins are a family of glycoproteins that are highly expressed in epithelial tissue cells. The main characteristic of mucins is the presence in their structure of widely glycosylated domains featuring very complex glycans. These carbohydrates bind to the peptide backbone through -O-glycosidic bonds with threonine and serine residues, being the first carbohydrate N-acetylgalactosamine (GalNAc). Notably, significant changes in the glycosylation patterns of MUC1 occur in tumor cells, which is associated with the exposure of antigens that are masked in the molecules present in healthy tissues. This characteristic opens the possibility of using tumor-associated MUC1 as a therapeutic target. Its incorporation in multicomponent vaccines can result in a robust immune response able to generate anti-MUC1 antibodies. Therefore, the main objective of this thesis is the design of antigens that present structural modifications capable of improving the affinity shown by the anti-MUC1 antibodies and with high immunogenicity and resistance to enzymatic hydrolysis. In this context, a methodology has been developed that allows stereoselective synthesis of a wide variety of S-glycosylcysteine derivatives. On the other hand, the critical elements for the molecular recognition of MUC1 type antigens by scFv-SM3 antibody have been studied in detail, explaining the differences found in recognition of Ser and Thr Tn antigens. These studies have motivated the design of synthetic routes that allows obtaining the building blocks of S-(α-D-GalNAc)-thiothreonine and Se-(α-D-GalNAc)- selenothreonine, which are ready-to-use in solid-phase peptide synthesis technique (SPPS). Moreover, it has been possible to demonstrate the capacity as the antigen of the unnatural peptide that incorporates the amino acid S-(α-D-GalNAc)-thiothreonine by formulating a therapeutic vaccine. Besides, a series of collaborations have been made with various research groups, nationally and internationally, to perform synthesis, purification and characterization of several peptides and glycopeptides.