Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay
The current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There hav...
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doaj-540d8ad9361745d1b4fc2ae7d12208212020-11-24T21:26:09ZengMDPI AGMolecules1420-30492018-09-01239233510.3390/molecules23092335molecules23092335Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation AssayMax Holzer0Nico Schade1Ansgar Opitz2Isabel Hilbrich3Jens Stieler4Tim Vogel5Valentina Neukel6Moritz Oberstadt7Frank Totzke8Christoph Schächtele9Wolfgang Sippl10Andreas Hilgeroth11Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103 Leipzig, GermanyInstitute of Pharmacy, Martin-Luther-University Halle-Wittenberg, 06120 Halle, GermanyInstitute of Pharmacy, Martin-Luther-University Halle-Wittenberg, 06120 Halle, GermanyDepartment for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103 Leipzig, GermanyDepartment for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103 Leipzig, GermanyDepartment for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103 Leipzig, GermanyDepartment for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103 Leipzig, GermanyDepartment of Neurology, University of Leipzig, Liebigstraße 20, 04103 Leipzig, GermanyProQinase GmbH Freiburg, Breisacher Straße 117, 79106 Freiburg, GermanyProQinase GmbH Freiburg, Breisacher Straße 117, 79106 Freiburg, GermanyInstitute of Pharmacy, Martin-Luther-University Halle-Wittenberg, 06120 Halle, GermanyInstitute of Pharmacy, Martin-Luther-University Halle-Wittenberg, 06120 Halle, GermanyThe current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There have been many approaches for a reduction of toxic Aβ peptides which mostly failed to halt cognitive deterioration in patients. The formation of neurofibrillary tangles (NFT) and its precursor tau oligomers have been suggested as main cause of neuronal degeneration because of a direct correlation of their density to the degree of dementia. Reducing of tau aggregation may be a viable approach for the treatment of AD. NFT consist of hyperphosphorylated tau protein and tau hyperphosphorylation reduces microtubule binding. Several protein kinases are discussed to be involved in tau hyperphosphorylation. We developed novel inhibitors of three protein kinases (gsk-3β, cdk5, and cdk1) and discussed their activity in relation to tau phosphorylation and on tau–tau interaction as a nucleation stage of a tau aggregation in cells. Strongest effects were observed for those inhibitors with effects on all the three kinases with emphasis on gsk-3β in nanomolar ranges.http://www.mdpi.com/1420-3049/23/9/2335AD drug discoverysynthesisderivativesstructure-activitylead structure |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Max Holzer Nico Schade Ansgar Opitz Isabel Hilbrich Jens Stieler Tim Vogel Valentina Neukel Moritz Oberstadt Frank Totzke Christoph Schächtele Wolfgang Sippl Andreas Hilgeroth |
spellingShingle |
Max Holzer Nico Schade Ansgar Opitz Isabel Hilbrich Jens Stieler Tim Vogel Valentina Neukel Moritz Oberstadt Frank Totzke Christoph Schächtele Wolfgang Sippl Andreas Hilgeroth Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay Molecules AD drug discovery synthesis derivatives structure-activity lead structure |
author_facet |
Max Holzer Nico Schade Ansgar Opitz Isabel Hilbrich Jens Stieler Tim Vogel Valentina Neukel Moritz Oberstadt Frank Totzke Christoph Schächtele Wolfgang Sippl Andreas Hilgeroth |
author_sort |
Max Holzer |
title |
Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay |
title_short |
Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay |
title_full |
Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay |
title_fullStr |
Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay |
title_full_unstemmed |
Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay |
title_sort |
novel protein kinase inhibitors related to tau pathology modulate tau protein-self interaction using a luciferase complementation assay |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2018-09-01 |
description |
The current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There have been many approaches for a reduction of toxic Aβ peptides which mostly failed to halt cognitive deterioration in patients. The formation of neurofibrillary tangles (NFT) and its precursor tau oligomers have been suggested as main cause of neuronal degeneration because of a direct correlation of their density to the degree of dementia. Reducing of tau aggregation may be a viable approach for the treatment of AD. NFT consist of hyperphosphorylated tau protein and tau hyperphosphorylation reduces microtubule binding. Several protein kinases are discussed to be involved in tau hyperphosphorylation. We developed novel inhibitors of three protein kinases (gsk-3β, cdk5, and cdk1) and discussed their activity in relation to tau phosphorylation and on tau–tau interaction as a nucleation stage of a tau aggregation in cells. Strongest effects were observed for those inhibitors with effects on all the three kinases with emphasis on gsk-3β in nanomolar ranges. |
topic |
AD drug discovery synthesis derivatives structure-activity lead structure |
url |
http://www.mdpi.com/1420-3049/23/9/2335 |
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