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@ARTICLE{Pickhardt:138183,
author = {Pickhardt, Marcus and Neumann, Thomas and Schwizer, Daniel
and Callaway, Kari and Vendruscolo, Michele and Schenk, Dale
and St George-Hyslop, Peter and Mandelkow, Eva M and Dobson,
Christopher M and McConlogue, Lisa and Mandelkow, Eckhard
and Tóth, Gergely},
title = {{I}dentification of {S}mall {M}olecule {I}nhibitors of
{T}au {A}ggregation by {T}argeting {M}onomeric {T}au {A}s a
{P}otential {T}herapeutic {A}pproach for {T}auopathies.},
journal = {Current Alzheimer research},
volume = {12},
number = {9},
issn = {1567-2050},
address = {Hilversum},
publisher = {Bentham Science Publ. Ltd.},
reportid = {DZNE-2020-04505},
pages = {814-828},
year = {2015},
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.},
keywords = {Animals / Benzothiazoles / Cell Line, Tumor / Cell
Survival: drug effects / Dose-Response Relationship, Drug /
Drug Evaluation, Preclinical / Fluorescent Dyes /
High-Throughput Screening Assays / Humans / Mice /
Microarray Analysis / Microscopy, Fluorescence / Molecular
Structure / Neuroprotective Agents: chemistry /
Neuroprotective Agents: pharmacology / Protein Aggregates:
drug effects / Protein Multimerization: drug effects /
Tauopathies: drug therapy / Tauopathies: metabolism /
Thiazoles / tau Proteins: genetics / tau Proteins:
metabolism / Benzothiazoles (NLM Chemicals) / Fluorescent
Dyes (NLM Chemicals) / MAPT protein, human (NLM Chemicals) /
Neuroprotective Agents (NLM Chemicals) / Protein Aggregates
(NLM Chemicals) / Thiazoles (NLM Chemicals) / tau Proteins
(NLM Chemicals) / thioflavin T (NLM Chemicals)},
cin = {AG Mandelkow 1 / AG Mandelkow 2},
ddc = {610},
cid = {I:(DE-2719)1013014 / I:(DE-2719)1013015},
pnm = {342 - Disease Mechanisms and Model Systems (POF3-342)},
pid = {G:(DE-HGF)POF3-342},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:26510979},
pmc = {pmc:PMC4976804},
doi = {10.2174/156720501209151019104951},
url = {https://pub.dzne.de/record/138183},
}