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

Descripción del proyecto

Combinar la química de superácidos con la glicociencia para acelerar el descubrimiento de fármacos

Los hidratos de carbono son macromoléculas complejas que participan en numerosos procesos biológicos y requieren un amplio conjunto de enzimas activas en hidratos de carbono para su síntesis y deterioro. Sin embargo, la falta de inhibidores de alta selectividad que modulen su actividad obstaculiza el descubrimiento de nuevos fármacos potentes y seguros. Financiado por las Acciones Marie Skłodowska-Curie, en el proyecto GLYCOMIMIC se utilizará la química de superácidos para obtener más datos sobre los estados de transición de las enzimas activas en hidratos de carbono y contribuirá al diseño de inhibidores potentes de dichas enzimas.

Objetivo

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.