FWF - Alterserkrankungen - New Glycomimetics for managing of age related diseases

The enzyme O-GlcNAcase removes oxygen-bound ß-D-glucosaminide residues from serine and threonine residues in glycoproteins enabling O-phosphorylation at the liberated sites. Too many phosphates - “hyperphosphorylation” - is one of the hallmarks of Alzheimer’s disease at the molecular level. Consequently, efficient inhibitors of O-GlcNAcase may serve as protecting agents against glycohydrolysis and subsequent phosphorylation thus interfering with the pathological phosphorylation process. A vital prerequisite of such enzyme inhibitors as pharmacological compounds is their high selectivity for the defined enzyme O-GlcNAcase over all other hexosaminidases most of which being essential for healthy life. We have substantial evidence that cyclopentane-derived sugar analogs may be highly potent inhibitors providing such high selectivity for the enzyme under consideration here. The project is concerned with the synthesis and screening of a telling range of these inhibitors emphasizing their blood-brain-barrier permeability and their oligomeric presentation on neoglycopetides.