Age-related defects in maintaining proteostasis are thought to be major contributing factors to Alzheimer's disease. This allows the build-up of toxic, amyloidogenic proteins such as phosphorylated Tau. One such defect is declining proteasome activity with age. Therefore, there is great interest in the development of agonists of the proteasome-mediated turnover of mis-folded proteins as a pharmacological strategy to treat Alzheimer?s disease, or at least delay its onset. Unfortunately, progress has been frustratingly slow and very few small molecule agonists are currently available, none of which are potent. This R21 proposal asks for support to apply both novel chemistry and an innovative screening assay to solve this problem. If successful, this project will set the stage for a chemical biology-based exploration of the utility of proteasome stimulation in combating Alzheimer?s disease.
The accumulation of mis-folded proteins results in the formation of cytotoxic, amyloidogenic aggregates, which is thought to contribute significantly to Alzheimer's disease. There is considerable interest in exploring the idea that stimulation of proteasome activity would counter this build-up, but no potent small molecule proteasome agonists are available. This R21 proposal seeks funding to support a novel screen by which hundreds of thousands of conformationally restricted oligomers will be assayed for proteasome binding as well as bona fide stimulation of the turnover of physiologically relevant, mis-folded proteins, including hyper-phosphorylated Tau, which is thought to be a major contributor to Alzheimer?s Disease.
| Erharuyi, Osayemwenre; Simanski, Scott; McEnaney, Patrick J et al. (2018) Screening one bead one compound libraries against serum using a flow cytometer: Determination of the minimum antibody concentration required for ligand discovery. Bioorg Med Chem Lett 28:2773-2778 |
| Shu, Keitou; Kodadek, Thomas (2018) Solid-Phase Synthesis of ?-Hydroxy Ketones Via DNA-Compatible Organocatalytic Aldol Reactions. ACS Comb Sci 20:277-281 |
