Glycoproteins with homogeneous glycosylation to define unexplored lectin binding properties

Descrizione del progetto

Decodifica della specificità delle lectine per la glicobiologia del cancro

La glicosilazione anomala, cioè il legame degli zuccheri alle proteine e ai lipidi, è una caratteristica distintiva del cancro. Le lectine sono proteine in grado di legarsi ai carboidrati, presenti nella maggior parte degli organismi viventi, e si sono rivelate strumenti preziosissimi nella ricerca sul cancro. Con il sostegno del programma di azioni Marie Skłodowska-Curie, il progetto GlycoScope mira a far luce sul legame delle lectine con modelli di glicosilazione finora inesplorati nel contesto del cancro. Il progetto integrerà le conoscenze molecolari a livello atomico ottenute tramite la spettroscopia di risonanza magnetica nucleare con i test funzionali basati sulle lectine, ampiamente utilizzati. Avvalendosi di metodi chemoenzimatici, GlycoScope sintetizzerà glicoproteine pure con modificazioni zuccherine omogenee e presenti in natura, eliminando così l’eterogeneità che costituisce un fattore di confusione nei sistemi naturali. I risultati contribuiranno al progresso di questo importante settore della glicobiologia oncologica.

Obiettivo

GlycoScope aims to provide key answers for the understanding of lectin binding to complex and previously unexplored glycosylation patterns related to cancer. Main aim is to integrate atomic-level insights into molecular recognition, obtained through Nuclear Magnetic Resonance (NMR) spectroscopy, with widely used lectin-based assays for glycosylation analysis. This combined strategy will enable a precise chemical definition of lectin specificities and refine one of the most commonly applied tools in glycosciences. To achieve this, and as a major challenge, pure glycoproteins presenting homogeneous glycoepitopes will be generated through chemoenzymatic synthesis, ensuring natural glycan presentation and providing the optimal platform for lectin-based assays, while overcoming the critical drawback of heterogeneity that characterizes natural glycosylation. Polylactosamine (PLN) modification through I-branching and terminal sialylation will be interrogated for their binding to PLN- binding lectins, including plant lectins commonly used to characterize glycosylation and galectins, immune lectins involved in health and disease.
Complementary, GlycoScope offers Dr. Soriano a unique opportunity to broaden his training beyond his current focus on natural products and synthetic chemistry. It will provide him with interdisciplinary expertise in Molecular Recognition, Biological Chemistry and Glycobiology, thereby greatly enhancing his future employability and broadening his scientific perspective. Alongside the acquisition of specific technical skills—including NMR-based molecular recognition, chemoenzymatic chemistry, and molecular biology and protein biochemistry—Dr. Soriano will also benefit from the outstanding scientific environment and advanced training opportunities available at CIC bioGUNE. At the same time, the host-group will highly benefit from Dr. Sorianos´ expertise in chemical synthesis and purification procedures, key for the development of the project.