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Structure-based discovery of small molecules that disaggregate Alzheimer's disease tissue derived tau fibrils in vitro.

<div class='caption-title'>CryoEM structure of AD-tau PHF in complex with EGCG.</div>
<div class='caption-title'>In silico and in vitro screening of tau disaggregants using EGCG pharmacophore.</div>
<div class='caption-title'>Characterization of tau disaggregation by lead compounds.</div>
Seidler PM, Murray KA, Boyer DR, Ge P, Sawaya MR, Hu CJ, Cheng X, Abskharon R, Pan H, DeTure MA, Williams CK, Dickson DW, Vinters HV, Eisenberg DS
OpenAccess logo Nat Commun 13 5451 (2022)
Related entries: 7upf, 7upg

Cited: 36 times
EuropePMC logo PMID: 36114178

Abstract

Alzheimer's disease (AD) is the consequence of neuronal death and brain atrophy associated with the aggregation of protein tau into fibrils. Thus disaggregation of tau fibrils could be a therapeutic approach to AD. The small molecule EGCG, abundant in green tea, has long been known to disaggregate tau and other amyloid fibrils, but EGCG has poor drug-like properties, failing to fully penetrate the brain. Here 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. This work suggests the potential of structure-based, small-molecule drug discovery for amyloid diseases.

Reviews - 7upe mentioned but not cited (1)

  1. Insights into the Structural Conformations of the Tau Protein in Different Aggregation Status. Pinzi L, Bisi N, Sorbi C, Franchini S, Tonali N, Rastelli G. Molecules 28 4544 (2023)

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  1. RNA as a component of scrapie fibrils. Bridges LR. Sci Rep 14 5011 (2024)
  2. research-article Replicating RNA as a component of scrapie fibrils. Bridges LR. bioRxiv 2023.08.17.553578 (2023)


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