Neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s (PD) have a high prevalence in the geriatric population and devastating psychological and socio-economical impacts. From a pathological standpoint, AD and PD share the hallmark of intracellular inclusion formation and post-synaptic accumulation of misfolded, prone-to-aggregate proteins capable of propagation. AD involves the misfolding of amyloid-beta, which forms Aβ plaques, and tau, which is responsible for the formation of neurofibrillary tangles. In PD, alpha-synuclein misfolds and forms inclusions called Lewy bodies in neurons located at critical brainstem nuclei involved in the control of fine motor movements. The discovery of small molecules exerting a multitargeted effect on prone-to-aggregate neuropeptides may lead to disease-modifying treatments for these devastating neurodegenerative disorders. Our drug discovery project is centered on alpha-synuclein and the 2N4R isoform of tau. The anti-aggregation and cellular protection activities of newly synthesized small molecules were evaluated with biophysical methods, such as thioflavin T fluorescence assays, photo-induced cross-linking of unmodified proteins, and dynamic light scattering, as well as survival assays with human neuroblastoma SH-SY5Y cells. We identified compounds that inhibit the aggregation and cytotoxicity of tau and alpha-synuclein and, therefore, serve as general aggregation inhibitors with broader applications for drug discovery and development relevant to AD and PD. This research provides insight into a multi-target phenotypic approach to alleviate the neurotoxicity of prone-to-aggregate proteins such as tau and alpha-synuclein. Specifically, the compounds identified here provide molecular scaffolds for further optimization and pre-clinical studies focused on drug development for neurodegenerative diseases.

Discovery of small molecules with dual effect on alpha-synuclein and tau isoform 2N4R fibrillization

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.