Structurally constrained mimetics of tumor-associated MUC1 antigens

Mucins are high molecular weight glycoproteins largely expressed by endothelial cells. They represent a physical protection for organs, against harmful species. When normal mucin become tumoral, a pathological oversimplification of the glycosidic portions occurred and saccharides, normally hidden, become exposed. These neo-glycans, called mucin-associated antigens, are interesting targets for the development of therapeutic cancer vaccines because of their almost exclusive presence on cancer cells. In particular, the structurally simple antigens associated to mucine-1 (MUC-1), namely antigen Tn, TF and STn, have been proved to be involved in tumour escape and metastasis. Recent studies showed a clear relationship between the presentation of these antigens and the amino acid involved in the glycosidic linkage; in particular the Thr residue induces a better presentation of the antigen with respect to Ser. In this context, the design of analogues and mimetics of these antigens offer an intriguing strategy to overcome the two main drawbacks affecting the natural derivatives: (a) low immunogenicity and, (b) reduced metabolic stability. In this project we aim at synthesizing structural mimetics of the antigenic TnThr, TFThr, STnThr and at employing these new compounds to decorate multivalent systems to study their in-vitro and in-vivo properties.