Identification of Small Molecule Inhibitors of Tau Aggregation by Targeting Monomeric Tau As a Potential Therapeutic Approach for Tauopathies.
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.
Marcus
M
Pickhardt
Thomas
T
Neumann
Daniel
D
Schwizer
Kari
K
Callaway
Michele
M
Vendruscolo
Dale
D
Schenk
Peter
P
St George-Hyslop
Eva M
EM
Mandelkow
Christopher M
CM
Dobson
Lisa
L
McConlogue
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany. mand@mpasmb.desy.de.
Eckhard
E
Mandelkow
Department of Clinical Neuroscienes, Wolfson Brain Imaging Center, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom. gt293@cam.ac.uk.
Gergely
G
Tóth
D000818:Animals; D052160:Benzothiazoles; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005456:Fluorescent Dyes; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D046228:Microarray Analysis; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D024801:Tauopathies / Q000188:drug therapy* / Q000378:metabolism*; D013844:Thiazoles; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D052160:Benzothiazoles; D005456:Fluorescent Dyes; C054369:MAPT protein, human; D018696:Neuroprotective Agents; D066329:Protein Aggregates; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T