Structure-based Discovery of Small Molecules that Disaggregate Tau Fibrils from Alzheimer’s Disease

Failing the development of effective drugs for Alzheimer’s disease (AD), millions are destined to die with dementia. AD is the consequence of neuronal death and brain atrophy associated with the aggregation of protein tau into fibrils. This suggests that disaggregation of tau fibrils could be a therapeutic approach to AD. The capacity for the polyphenolic small molecule EGCG, abundant in green tea, to disaggregate tau and other amyloid fibrils has long been known, but EGCG has poor drug-like properties and fails to fully penetrate the brain. Here we have cryogenically trapped a high-energy 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 tau fibrils. This work suggests the potential of structure-based, small-molecule drug discovery for amyloid diseases, perhaps portending chemical interventions for Alzheimer’s akin to those so effective for treating cancer and metabolic disorders.