Ioannis D. Kostas - Research

β-D-GLUCOPYNANOSYL-THIOSEMICARBAZONE DERIVATIVES AS INHIBITORS OF GLYCOGEN PHOSPHORYLASE

Glucose derivatives are selective and efficient catalytic inhibitors of glycogen phosphorylase (GP), a target for the design of type 2 diabetes therapeutics. On the other hand, thiosemicarbazones are promising compounds in many diseases, in particular cancer. The present work (in collaboration with Dr. N.G. Oikonomakos) is aiming to combine these two classes of compounds into one family of organic molecules, and thus a series of β-D-glucopyranosyl-modified thiosemicarbazones have been synthesized. Kinetic experiments showed inhibition (IC50 ~90 μM (minimum)) of GP, while crystallographic results for the GP - glucose-thiosemicarbazone complex showed that these derivatives surprisingly bind at the new allosteric site rather than the catalytic site, and stabilise the less active quaternary conformation of the enzyme.
This investigation is part of the project EURODESY: A European Research Training Site for the Design and Synthesis of Novel Neuroprotective and Hypoglycaemic Agents through a Multi-disciplinary approach. EURODESY is funded by Marie Curie Early Stage Training program (EST).