Next generation development and target identification of OGA Inhibitors for the treatment of Alzheimer’s Disease

• Applicant: Dr. Johannes Lehmann
• Subject Area: Biological and Biomimetic Chemistry ; Organic Molecular Chemistry - Synthesis and Characterisation ; Pharmacy
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 390020971

Alzheimer’s disease is a chronic neurodegenerative sickness with a steadily increasing number of patients. Currently, only symptomatic therapies for AD exist and the development of disease modifying treatments has proven challenging and requires the development of novel therapeutic strategies. A possible starting point is the inhibition of O-GlcNAcase (OGA). This enzyme counterbalances protein glycosylation, a cellular protection mechanism to hyperphosphorylation. Opposing to phosphorylation, which is a directed post-translational protein modification that serves as cellular signaling response, hyperphosphorylation is a non-directed pathogenic process, which can lead to protein unfolding and co-occurs to Alzheimer. Therefore, maintenance of protein glycosylation through OGA inhibition may be an important feature to avoid hyperphosphorylation of proteins and prevent Alzheimer’s disease progression. In order to act on neuronal cells and to interfere with OGA drug molecules must cross the blood-brain barrier, limiting therapeutic strategies to small molecular compounds. A primary class of OGA blockers bares structural similarities to the sugar substrate and effectively block the active site. Unfortunately, these molecules show limited permeability, low serum stability. A second class of OGA inhibitors are iminocyclitols, pyrrolidine based iminosugars. Despite their therapeutic potential, the challenging synthesis of this compound class has complicated their development. I propose to synthesize a wide variety of novel iminocyclitols with enhanced pharmacokinetic properties by modifying an already established procedure from the Britton lab. To overcome issues with poor compound stability in blood serum and cell permeability I will evaluate the influence of fluoro- and trifluoromethyl-substituents at various positions within the structure. In addition, the incorporation of so-called bioisosteres, structural motifs that mimic functional groups but lack their typical reactivity, are to be tested. Furthermore, compounds bearing a terminal alkyne are anticipated. This functionality will enable rapid analogue generation by either conversion to a triazole using click-chemistry or Sonogashira cross-coupling reactions. Additionally, these molecules will be used as molecular probes in live-cell assays. Upon binding to interaction partners UV-irradiation of a photocrosslinker will create covalent bond formation to molecules in spatial proximity. The application of this strategy on cellular level should reveal interacting proteins. Using already established collaborations to partners in protein crystallography and biological chemistry, I will play a key role in this interdisciplinary project. Overall, this study will contribute Alzheimer’s research by generation of novel OGA inhibitors with improved pharmacokinetic properties and proteomic data to determine cellular interactions for clinical trials.

• DFG Programme: Research Fellowships
• International Connection: Canada
• Host: Professor Dr. Robert Britton