Journal Article

DZNE-2020-04505

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Identification of Small Molecule Inhibitors of Tau Aggregation by Targeting Monomeric Tau As a Potential Therapeutic Approach for Tauopathies.

Pickhardt, M. (First author)DZNE* ; Neumann, T. ; Schwizer, D. ; Callaway, K. ; Vendruscolo, M. ; Schenk, D. ; St George-Hyslop, P. ; Mandelkow, E. M.DZNE* ; Dobson, C. M. ; McConlogue, L. ; Mandelkow, E.DZNE* ; Tóth, G. (Corresponding author)

2015
Bentham Science Publ. Ltd. Hilversum

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Please use a persistent id in citations: doi:10.2174/156720501209151019104951

Abstract: A potential strategy to alleviate the aggregation of intrinsically disordered proteins (IDPs) is to maintain the native functional state of the protein by small molecule binding. However, the targeting of the native state of IDPs by small molecules has been challenging due to their heterogeneous conformational ensembles. To tackle this challenge, we applied a high-throughput chemical microarray surface plasmon resonance imaging screen to detect the binding between small molecules and monomeric full-length Tau, a protein linked with the onset of a range of Tauopathies. The screen identified a novel set of drug-like fragment and lead-like compounds that bound to Tau. We verified that the majority of these hit compounds reduced the aggregation of different Tau constructs in vitro and in N2a cells. These results demonstrate that Tau is a viable receptor of drug-like small molecules. The drug discovery approach that we present can be applied to other IDPs linked to other misfolding diseases such as Alzheimer's and Parkinson's diseases.

Keyword(s): Animals (MeSH) ; Benzothiazoles (MeSH) ; Cell Line, Tumor (MeSH) ; Cell Survival: drug effects (MeSH) ; Dose-Response Relationship, Drug (MeSH) ; Drug Evaluation, Preclinical (MeSH) ; Fluorescent Dyes (MeSH) ; High-Throughput Screening Assays (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Microarray Analysis (MeSH) ; Microscopy, Fluorescence (MeSH) ; Molecular Structure (MeSH) ; Neuroprotective Agents: chemistry (MeSH) ; Neuroprotective Agents: pharmacology (MeSH) ; Protein Aggregates: drug effects (MeSH) ; Protein Multimerization: drug effects (MeSH) ; Tauopathies: drug therapy (MeSH) ; Tauopathies: metabolism (MeSH) ; Thiazoles (MeSH) ; tau Proteins: genetics (MeSH) ; tau Proteins: metabolism (MeSH) ; Benzothiazoles ; Fluorescent Dyes ; MAPT protein, human ; Neuroprotective Agents ; Protein Aggregates ; Thiazoles ; tau Proteins ; thioflavin T

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Contributing Institute(s):

1. Structural Principles of Neurodegeneration (AG Mandelkow 1)
2. Cell and Animal Models of Neurodegeneration (AG Mandelkow 2)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2015

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Database coverage:
; BIOSIS Previews ; BIOSIS Reviews Reports And Meetings ; Clarivate Analytics Master Journal List ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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