Unnatural glycopeptides with application on cancer research
Protein glycosylation is the most frequent post-translational modification which mediates a variety of cellular processes. In addition, changes in protein glycosylation can modulate cellular phenotypes such as growth, development, and disease. Therefore, the main objective of the present PhD dissertation will be focus on the study of two important classes of O-glycopeptides with relevant implications to fight against cancer: mucins, such as mucin-1 (MUC1), and antifreeze glycoproteins. Concerning the first mentioned class, mucins are a family of O-glycoproteins with high molecular weight that serve as cell-surface receptors and sensors. Notably, aberration in the glycosylation of this tandem repeats is observed in human carcinomas, which made mucins excellent candidates for the development of novel tools for cancer vaccination or early cancer detection. Despite the vast amount of clinical and immunological data available on anti-MUC1 antibodies, the molecular details by which these antibodies recognize their targets are scarce. This information is essential, for example, to develop new MUC1 glycopeptides with improved binding strength and specificity for anti-MUC1 antibodies that can be used in early cancer detection assays. On this basis, an exhaustive study of the molecular basis by which two important anti-MUC1 antibodies (SM3 and 5E5) interact with their target has been performed. In this sense, rational structure-based modifications on the antigen structure have been carried out achieving more efficient antigens in terms of affinity for anti-MUC1 antibodies. Furthermore, a serologic study based on a nanoparticle dot-blot assay was performed observing significant differences between healthy patients and patients with cancer when using these new unnatural glycopeptides. On the other hand, antifreeze glycoproteins have recently attracted interest due to their use as crystal inhibitors for applications such as tumor cryotherapy. However, the mechanism of action of these glycoproteins is currently unclear. On this basis, various antifreeze glycopeptide derivatives have been synthesized to understand the mechanism by which natural antifreeze glycoproteins can act as potent inhibitors of ice formation.
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