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

Paul M. Seidler, Kevin A. Murray, David R. Boyer, Peng Ge, Michael R. Sawaya, Carolyn J. Hu, Xinyi Cheng, Romany Abskharon, Hope Pan, Michael A. DeTure, Christopher K. Williams, Dennis W. Dickson, Harry V. Vinters and David S. Eisenberg ()
Additional contact information
Paul M. Seidler: UCLA
Kevin A. Murray: UCLA
David R. Boyer: UCLA
Peng Ge: UCLA
Michael R. Sawaya: UCLA
Carolyn J. Hu: UCLA
Xinyi Cheng: UCLA
Romany Abskharon: UCLA
Hope Pan: UCLA
Michael A. DeTure: Mayo Clinic
Christopher K. Williams: David Geffen School of Medicine, UCLA
Dennis W. Dickson: Mayo Clinic
Harry V. Vinters: David Geffen School of Medicine, UCLA
David S. Eisenberg: UCLA

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
References: View complete reference list from CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-32951-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32951-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-32951-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().