TY  - JOUR
AU  - Pickhardt, Marcus
AU  - Neumann, Thomas
AU  - Schwizer, Daniel
AU  - Callaway, Kari
AU  - Vendruscolo, Michele
AU  - Schenk, Dale
AU  - St George-Hyslop, Peter
AU  - Mandelkow, Eva M
AU  - Dobson, Christopher M
AU  - McConlogue, Lisa
AU  - Mandelkow, Eckhard
AU  - Tóth, Gergely
TI  - Identification of Small Molecule Inhibitors of Tau Aggregation by Targeting Monomeric Tau As a Potential Therapeutic Approach for Tauopathies.
JO  - Current Alzheimer research
VL  - 12
IS  - 9
SN  - 1567-2050
CY  - Hilversum
PB  - Bentham Science Publ. Ltd.
M1  - DZNE-2020-04505
SP  - 814-828
PY  - 2015
AB  - 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.
KW  - Animals
KW  - Benzothiazoles
KW  - Cell Line, Tumor
KW  - Cell Survival: drug effects
KW  - Dose-Response Relationship, Drug
KW  - Drug Evaluation, Preclinical
KW  - Fluorescent Dyes
KW  - High-Throughput Screening Assays
KW  - Humans
KW  - Mice
KW  - Microarray Analysis
KW  - Microscopy, Fluorescence
KW  - Molecular Structure
KW  - Neuroprotective Agents: chemistry
KW  - Neuroprotective Agents: pharmacology
KW  - Protein Aggregates: drug effects
KW  - Protein Multimerization: drug effects
KW  - Tauopathies: drug therapy
KW  - Tauopathies: metabolism
KW  - Thiazoles
KW  - tau Proteins: genetics
KW  - tau Proteins: metabolism
KW  - Benzothiazoles (NLM Chemicals)
KW  - Fluorescent Dyes (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
KW  - Neuroprotective Agents (NLM Chemicals)
KW  - Protein Aggregates (NLM Chemicals)
KW  - Thiazoles (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - thioflavin T (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26510979
C2  - pmc:PMC4976804
DO  - DOI:10.2174/156720501209151019104951
UR  - https://pub.dzne.de/record/138183
ER  -