Gaining insights into Enzymes Transition States: Superacid as new tool to design specific CAZymes inhibitors.

Descrizione del progetto

Abbinare la chimica dei superacidi e la glicoscienza per velocizzare la scoperta dei farmaci

I carboidrati sono macromolecole complesse coinvolte in molti processi biologici che richiedono un’ampia serie di enzimi carboidrati-attivi per la loro sintesi e decomposizione. Tuttavia, la mancanza di inibitori ad alta selettività in grado di modulare la loro attività, ostacola la scoperta di nuovi agenti terapeutici potenti e sicuri. Il progetto GLYCOMIMIC, finanziato dal programma di azioni Marie Skłodowska-Curie, si avvarrà della chimica dei superacidi per acquisire ulteriori informazioni sugli stati di transizione degli enzimi carboidrati-attivi e supporterà la progettazione di potenti inibitori di tali enzimi.

Obiettivo

Glycosciences study the structural and functional roles of carbohydrates in biology and have an increasing impact on many areas of our economy (health, food, natural resources). Carbohydrate Active enZymes (CAZymes), which catalyse the assembly (Glycosyl transferases, GTs) and breakdown (Glycosidases, GHs) of glycosidic linkage in carbohydrates, are essential to life, being involved in key cell functions. Their pharmacological modulation by means of selective CAZymes’ inhibitors can have multiple applications (e.g. antiviral TamifluTM, antidiabetic GlysetTM, molecular chaperone GalafoldTM). However, the design of inhibitors endowed of high selectivity is challenging, representing the major obstacle in discovering new potent and safe therapeutic agents targeting CAZymes. In this context, GLYCOMIMIC offers an innovative approach based on superacid chemistry to gain insights into CAZymes’ transition states (TS) and to help the design of specific inhibitors, paving the way for short-term impact on drug discovery! Superacid chemistry is only mastered by very few research groups in the world and is a European specificity of the Institute of Chemistry of Poitiers (IC2MP - UMR CNRS 7285 – France) and will be applied for the first time to glycosciences. With Univ. Barcelona (world leader in computer simulation of biological processes at atomic-electronic detail) acting as secondment, GLYCOMIMIC blends multidisciplinary states of the art research training in carbohydrate chemistry, superacids, low-temperature NMR analysis, DFT calculations, QM/MM dynamic simulation of enzymes and enzyme inhibition studies. It will provide a prolific fellow with an internationally competitive training, with the aim of advancing the career of an autonomous scientist in the EU and the next generation of multidisciplinary researchers in (bio)pharmaceutical sciences.