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

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

  • Nat Commun. 2022 Sep 16;13(1):5451. doi: 10.1038/s41467-022-32951-4.
Paul M Seidler # 1 2 3 4 5 6,  Kevin A Murray # 1 2 3 4 5,  David R Boyer # 1 2 3 4 5,  Peng Ge 1 2 3 4 5,  Michael R Sawaya 1 2 3 4 5,  Carolyn J Hu 1 2 3 4 5,  Xinyi Cheng 1 2 3 4 5,  Romany Abskharon 1 2 3 4 5,  Hope Pan 1 2 3 4 5,  Michael A DeTure 7,  Christopher K Williams 8,  Dennis W Dickson 7,  Harry V Vinters 8 9,  David S Eisenberg 10 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, USA.
  • 2 Department of Biological Chemistry, UCLA, Los Angeles, CA, USA.
  • 3 UCLA-DOE Institute, Los Angeles, CA, USA.
  • 4 Molecular Biology Institute, UCLA, Los Angeles, CA, USA.
  • 5 Howard Hughes Medical Institute, Los Angeles, CA, USA.
  • 6 Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA.
  • 7 Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  • 8 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
  • 9 Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
  • 10 Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, USA. david@mbi.ucla.edu.
  • 11 Department of Biological Chemistry, UCLA, Los Angeles, CA, USA. david@mbi.ucla.edu.
  • 12 UCLA-DOE Institute, Los Angeles, CA, USA. david@mbi.ucla.edu.
  • 13 Molecular Biology Institute, UCLA, Los Angeles, CA, USA. david@mbi.ucla.edu.
  • 14 Howard Hughes Medical Institute, Los Angeles, CA, USA. david@mbi.ucla.edu.
  • # Contributed equally.
PMID: 36114178 DOI: 10.1038/s41467-022-32951-4
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.

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