New Glycomimetics for managing of age related diseases

The enzyme O-GlcNAcase removes oxygen-bound -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 Alzheimers 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.

Key aim of the project has been the preparation and biological testing of a new type of biologically active agents directed at the prevention of one particular molecular step in the development of age-related diseases, in particular, Alzheimer' disease. These substances are chemically related to a certain monosaccharide, N-acetyl-D-glucosamine, which is frequently found in Nature being bound to many proteins. Excessive enzymatic removal of this sugar from the protein (as can occur in certain diseases) results in many places where another enzyme can now place (too many) phosphate groups thus making the protein insoluble in water resulting in its precipitation around nerve tissue in the brain. This process is involved in the formation of so-called plaques in the brain of patients and is a key step in the outbrake of Alzheimer's. Preventing this so-called hyperphosphorylation protects the protein from becoming insoluble and toxic. Consequently, preventing the enzymatic removal of N-acetyl-D-glucosamine from the protein is a protective method to avoid the formation of the toxic insoluble plaques and may reduce and postpone development of age-related diseases in general and Alzheimer's inparticular. Substances prepared in the course of this project are a new type of such agents and could be shown to highly efficiently prevent the undesired removal of N-acetyl-D-glucosamine from the protein while being completely non-toxic and furthermore and importantly, being practically inert to other similar but highly important enzymes necessary for the health and well-being. The project has provided very important pieces of infomation for the activity improvement and the cheap preparation of these new agents for important medicinal in-depth follow-up investigations at molecular level with a clear view to lead compounds for the management of diseases such as Alzheimer's.