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- W4319917076 abstract "Alzheimer's disease (AD) and Parkinson's disease (PD) are the consequences of neuronal death associated with the aggregation, respectively of proteins tau and alpha-synuclein into amyloid fibrils. Thus disaggregation of these fibrils could be therapeutic approaches to these conditions. The small molecule EGCG, abundant in green tea, has long been known to disaggregate amyloid fibrils, but EGCG has poor drug-like properties, failing to fully penetrate the brain. To understand how EGCG can disaggregate stable fibrils, we have cryogenically trapped an intermediate of brain-extracted tau fibrils on the kinetic pathway to EGCG-induced disaggregation and have determined its cryoEM structure. The structure reveals that EGCG molecules stack in polar clefts between the paired helical protofilaments that pathologically define AD. Treating the EGCG binding position as a pharmacophore, we computationally screened thousands of drug-like compounds for compatibility for the pharmacophore, discovering several that experimentally disaggregate brain-derived tau fibrils in vitro and some that limit alpha-synuclein aggregation in vitro and in C. elegans. This work suggests the potential of structure-based, small-molecule drug discovery for amyloid diseases." @default.
- W4319917076 created "2023-02-11" @default.
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- W4319917076 date "2023-02-01" @default.
- W4319917076 modified "2023-10-01" @default.
- W4319917076 title "Structure-based discovery of small molecules that disaggregate amyloid fibrils from post-mortem Alzheimer's and Parkinson's brains" @default.
- W4319917076 doi "https://doi.org/10.1016/j.bpj.2022.11.1763" @default.
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