An identification of MARK inhibitors using high throughput MALDI-TOF mass spectrometry
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F22%3A73612578" target="_blank" >RIV/61989592:15110/22:73612578 - isvavai.cz</a>
Result on the web
<a href="https://www.sciencedirect.com/science/article/pii/S0753332221013366?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0753332221013366?via%3Dihub</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.biopha.2021.112549" target="_blank" >10.1016/j.biopha.2021.112549</a>
Alternative languages
Result language
angličtina
Original language name
An identification of MARK inhibitors using high throughput MALDI-TOF mass spectrometry
Original language description
MAP/micmtubule affinity-regulating kinases (MARKs) were recently identified as potential drug targets for Alzheimer's disease (AD) due to their role in pathological hyperphosphorylation of tau protein. Hyperphosphorylated tau has decreased affinity for microtubule binding, impairing their stability and associated functions. Destabilization of microtubules in neuronal cells leads to neumdegeneration, and microtubuleunbound tau forms neurofibrillary tangles, one of the primary hallmarks of AD. Many phosphorylation sites of tau protein have been identified, but phosphorylation at Ser(262) , which occurs in early stages of AD, plays a vital role in the pathological hyperphosphorylation of tau. It has been found that Ser(262) is phosphorylated by MARK4, which is currently an intensively studied target for treating Alzheimer's disease and other neurodegenerative diseases. Our present study aimed to develop a high throughput compatible assay to directly detect MARK enzymatic activity using echoacoustic transfer and MALDI-TOF mass spectrometer. We optimized the assay for all four isoforms of MARK and validated its use for identifying potential inhibitors by the screening of 1280 compounds from the LOPAC (R) 1280 International (Library Of Pharmacologically Active Compounds). Six MARK4 inhibitors with IC50 < 1 mu M were identified. To demonstrate their therapeutic potential, active compounds were further tested for MARK4 selectivity and ability to cross the blood-brain barrier. Lastly, the molecular docking with the most active inhibitors to predict their interaction with MARK4 was performed.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
BIOMEDICINE & PHARMACOTHERAPY
ISSN
0753-3322
e-ISSN
1950-6007
Volume of the periodical
146
Issue of the periodical within the volume
February 2022
Country of publishing house
FR - FRANCE
Number of pages
10
Pages from-to
112549
UT code for WoS article
000744602000002
EID of the result in the Scopus database
2-s2.0-85121204355